SK89798A3 - Substituted n-[(aminoiminomethyl)phenyl]propyl amides or n-[(aminomethyl)phenyl]propyl amides - Google Patents

Abstract

The compounds according to the invention are substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides of formula (I) herein which exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are Factor Xa inhibitors. The present invention is directed to compounds of formula (I), compositions containing compounds of formula (I), methods for their preparation and their use, which are for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.

Description

The compounds of formula I exhibit useful pharmacological activity and are therefore incorporated into pharmaceutical compositions and are used to treat patients suffering from certain medical disorders. In particular, they are inhibitors of factor Xa. The present invention is directed to compounds of Formula I, compositions comprising compounds of Formula I, and their use for treating patients suffering from or susceptible to conditions that can be ameliorated by administration of a Factor Xa inhibitor.

Factor Xa is the penultimate enzyme in the coagulation cascade. Both free factor Xa and factor Xa, which is part of the prothrombinase complex (factor Xa, factor Va, calcium and phospholipids) are inhibited by compounds of formula

I. Inhibition of factor Xa is achieved by direct complex formation between the inhibitor and the enzyme and is therefore independent of the antithrombin III plasma cofactor. Effective inhibition of Factor Xa is achieved by administering these compounds either orally, by continuous intravenous infusion, by a single intravenous administration, or by some other parenteral route that achieves the desired effect of preventing factor Xa induced thrombin formation from prothrombin.

Anticoagulant therapy is indicated for the treatment and prophylaxis of various thrombotic conditions in both the venous and arterial streams. In the arterial system, abnormal thrombus formation is mainly associated with coronary arteries,

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cerebral and peripheral streams. Diseases associated with thrombotic clogging of these vessels primarily include acute myocardial infarction (AIM), unstable angina, thromboembolism, acute vascular occlusion associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient stroke, coronary bypass (CABP) or peripheral arteries. Chronic anticoagulant therapy may also be useful to prevent vascular lumen constriction (restenosis), which often occurs following PTCA and CABG, and to maintain vascular accessibility in patients with long-term hemodialysis. As for the venous stream, pathological thrombus formation often occurs in the veins of the lower extremities following abdominal, knee and calf operations (deep vein thrombosis-DVT). DVT further makes the patient susceptible to more risk pulmonary thromboembolism. Systemic disseminated intravascular coagulopathy (DIK) usually occurs in both vascular systems in septic shock, certain viral infections, and tumor. This condition is characterized by rapid consumption of coagulation factors and their plasma inhibitors, resulting in the formation of life-threatening clots

in the microcirculation of various organ systems. The above indications include some, but not all, of the possible clinical situations in which anticoagulant therapy is warranted. Those skilled in the art are well aware of circumstances requiring either acute or chronic anticoagulant therapy.

SUMMARY OF THE INVENTION

Summary of the invention:

The present invention is directed to the pharmaceutical use of a compound of formula I below to reduce the production or physiological effects of factor Xa in the treatment of a patient suffering from a disease state associated with a physiologically harmful excess of factor Xa, wherein the compound has the following formula I:

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in which

R 1 and R ₂ represent a hydrogen atom or together form the group = NR ₉ ,

R 3 is -CO 2 R 6, -C (O) R 6, -CONR 6 R 6, -CH 2 OR 7 or -CH 2 R 7,

R 4 represents a group of the general formula

or

R ₄ is H, alkyl, cycloalkyl or cycloalkylalkyl group,

R ₆ represents an alkyl, alkenyl, optionally substituted aryl or optionally substituted heteroaryl group,

Re represents a hydrogen atom or a lower alkyl group,

R ₇ represents a hydrogen atom, a lower alkyl group, a lower acyl, aroyl or heteroaryl group,

R ₈ represents a hydrogen atom or a lower alkyl group,

R 8 is a group of formula R ₁₀ O ² C-, R ₁₀ O-, HO ·, cyano, R ₁₀ CO-, HCO-, lower alkyl, nitro or Y ¹ Y ² N-, wherein R ₁₀ is optionally substituted alkyl, optionally substituted aralkyl, or optionally a substituted heteroaralkyl group and wherein Y ¹ and Y ² independently represent a hydrogen atom or an alkyl group,

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A and B are hydrogen or together are a bond,

A represents an optionally substituted aryl group or an optionally substituted heteroaryl group and n is 0, 1 or 2, or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof.

Detailed description of the invention:

As used hereinabove and throughout the present disclosure, the following terms, unless otherwise indicated, should be understood as follows:

definitions:

A "patient" includes both human and other mammals.

"Alkyl" means a straight or branched aliphatic hydrocarbon group having about 1 to about 15 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the straight alkyl chain. "Lower alkyl" means about 1 to about 6 carbon atoms in the chain, which may be straight or branched. The alkyl group may be substituted by one or more halogen atoms, a cycloalkyl or cycloalkenyl group. Examples of alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, norm. propyl, isopropyl, norm. butyl, tert-butyl, norm. pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

Alkenyl means a straight or branched aliphatic hydrocarbon group having from about 2 to about 15 carbon atoms in the chain containing a carbon-carbon double bond. Preferred alkenyl groups have 2 to about 15 carbon atoms in the chain and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that either or

30997 / H several lower alkyl groups, such as methyl, ethyl or propyl, are attached to a straight alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group may be substituted by one or more halogen atoms. Examples of alkenyl groups include ethenyl, propenyl, norm. butenyl, isobutenyl, 3-methyl-2-butenyl, norm. pentenyl, heptenyl, octenyl and decenyl.

"Cycloalkyl" means a non-aromatic mono- or polycyclic ring system of about 3 to about 10 carbon atoms. Examples of monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group may be substituted by one or more halogen atoms, a methylene group (H ₂ C =) or an alkyl group. Examples of polycyclic cycloalkyl rings include 1-decalin, 1- or 2-adamantyl and norbornyl.

"Cycloalkenyl" means a non-aromatic mono- or polycyclic ring system of about 3 to about 10 carbon atoms containing a double bond between two carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl. An example of a polycyclic ring is norbornylenyl. The cycloalkenyl group may be substituted by one or more halogen atoms, a methylene group (H ₂ C =) or an alkyl group.

"Heterocyclic radical" means a non-aromatic monocyclic or polycyclic ring system of about 3 to about 10 carbon atoms. Preferred rings include about 5 to about 6 ring atoms, wherein one of the ring atoms represents an oxygen, nitrogen or sulfur atom. The heterocyclic radical may be optionally substituted with one or more halogen atoms. Preferred monocyclic heterocyclic ring radicals include pyrrole, tetrahydrothiophenyl and tetrahydrothiopyranyl. The sulfur or nitrogen containing heterocyclic moiety may also optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.

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Aryl means an aromatic carbocyclic radical containing from about 6 to about 10 carbon atoms. Examples of aryl groups include phenyl or naphthyl, optionally substituted with one or more aryl group substituents, which may be the same or different, wherein "aryl group substituents" include hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl , hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, carboxyl, acyl, aroyl, halogen, nitro, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aralkoxy, aralkoxy, aralkoxy, aralkoxy, aralkoxy, aralkoxy, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, aralkylthio, Y ¹ Y ² N, Y ¹ Y ² N-alkyl-, CO- or Y ¹ Y ² NSO ² -, wherein Y ¹ and Y ² independently represent hydrogen, alkyl an aryl, an aralkyl group. The Preferred aryl group substituents include hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, Y ¹ Y ² N-, Y ¹ Y ² NCO- or Y ¹ Y ² NSO ² -, wherein Y ¹ and Y ² independently represent a hydrogen atom and an alkyl group.

"Heteroaryl" means a monocyclic or polycyclic hydrocarbon ring system of about 5 to about 10 carbon atoms, wherein one or more of the ring carbon atoms is / are elements other than a carbon atom, such as nitrogen, oxygen or sulfur. A "heteroaryl group" may also be substituted with one or more aryl group substituents. Examples of heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazazolyl, quinolinyl, indolyl and isoquinolinyl.

"Aralkyl" means an arylalkyl group in which aryl and alkyl are as previously described. Preferred aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.

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Ί "Hydroxyalkyl" means a group of the formula ΗΟ -alkyl- in which the alkyl group is as previously described. Preferred hydroxyalkyl groups contain a lower alkyl group. Examples of hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means a group of the formula HCO- or alkyl-CO-, in which the alkyl group is as previously described. Preferred acyl groups contain a lower alkyl group. Examples of acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.

"Aroyl" means an aryl-CO- group in which the alkyl group is as previously described. Examples of groups include benzoyl, 1-naphthoyl and 2-naphthoyl.

"Alkoxy" means an alkyl-alkyl- group in which the alkyl group is as previously described. Examples of alkoxy groups include methoxy, ethoxy, norm. propoxy, isopropoxy, norm. butoxy and heptoxy.

"Aryloxy" means an aryl-aryl- group in which the aryl group is as previously described. Examples of aryloxy groups include phenoxy and naphthoxy.

"Aralkyloxy" means an aralkyl-Ο- group in which the aralkyl group is as previously described. Examples of aralkyloxy include benzyloxy and 1- or 2-naphthalenomethoxy.

"alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Examples of alkylthio include methylthio, ethylthio, isopropylthio and heptylthio.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Examples of arylthio groups include phenylthio and naphthylthio.

"Aralkylthio" means a group of the formula aralkyl-S-, in which the aralkyl group is as previously described. An example of aralkylthio is benzylthio.

_{30997/1 i} H ^{Y1 Y2} N- "means a substituted or unsubstituted amino group, wherein Y ¹ and Y ² are as previously described. Examples of the group include amino (H ₂ N-), methylamino, ethylamino, dimethylamino and diethylamino.

Alkoxycarbonyl means an alkyl-O-CO- group. Examples of alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.

Aryloxycarbonyl means an aryl-O-CO- group. Examples of aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

"Alkoxycarbonyl" means an aralkyl-O-CO- group. An example of an aralkoxycarbonyl group is a benzyloxycarbonyl group.

_i , Y ¹ Y ² NCO- "means a substituted or unsubstituted carbamoyl group in which Y ¹ and Y ² are as previously described. Examples of groups are carbamoyl (H 2 NCO-) and dimethylaminocarbamoyl (Me ₂ NCO-).

"Y ¹ Y ² NSO ² -" means a substituted or unsubstituted sulfamoyl group in which Y ¹ and Y ² are as previously described. Examples of groups are the aminosulfamoyl group (H ₂ NSO ₂ -) and the dimethylaminosulfamoyl group (Me ₂ NSO ₂ -).

"Acylamino" means a group of the formula acyl-ΝΗ-, in which the acyl group is as defined herein.

"Aroylamino" means aroyl-NH- group in which the aroyl group is as defined herein.

"Alkylsulfonyl" means an alkyl-SO ₂ - group.

Preferred groups are those in which the alkyl group is lower alkyl.

30997 / H "Alkylsulfinyl" means an alkyl-SO- group. Preferred groups are those in which the alkyl group is lower alkyl.

Arylsulfonyl means an aryl-SO2- group.

"Arylsulfinyl" means an aryl-SO- group.

"Halogen" means a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine atoms are preferred, and fluorine or chlorine atoms are more preferred.

"Prodrug prodrug" means a compound that may or may not be biologically active by itself, but which can be converted to a biologically active chemical by metabolic, solvolytic or other physiological means.

Preferred embodiments of the invention:

A preferred embodiment of the present invention is a method of treating a disease state capable of being alleviated by inhibiting factor Xa production by an effective amount of a compound of Formula I in a patient suffering from the disease state.

A preferred embodiment of a compound of the invention is a compound of formula I wherein R 1 and R 2 together form = NH.

Another preferred embodiment of a compound of the invention is a compound of formula I wherein R ₃ is -CO 2 R ₆ . -CH ₂ OR 7 or -CH ₂ SR ₇ .

Another preferred embodiment of a compound of the invention is a compound of formula I wherein n is 1.

Another preferred embodiment of a compound of this invention is a compound of formula I wherein R ₃ is -CO 2 R 6 and R 6 is lower alkyl.

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Another preferred embodiment of a compound of the invention is a compound of formula I wherein R ₃ is -CH ₂ OR 7 or -CH ₂ SR ₇ and R _{6 is} -CH ₂ OR ₇ . represents a hydrogen atom or a lower alkyl.

Another preferred embodiment of the compound of the invention is a compound of formula I wherein R 1 and R ₂ together are = NH and form an aminoiminomethyl group on the phenyl moiety that is in the meta position relative to the attachment position of the phenyl moiety to the propyl moiety.

Another preferred embodiment of a compound of the invention is a compound of formula I wherein Ar is an optionally substituted aryl group.

Another preferred embodiment of a compound of the invention is a compound of formula I wherein Ar is phenyl.

Another preferred embodiment of a compound of this invention is a compound of formula I wherein R ₅ is an optionally substituted phenyl, an optionally substituted biphenyl, an optionally substituted naphthyl, or an optionally substituted heterobiphenyl.

Another preferred embodiment of a compound of the invention is a compound of formula I wherein R ₁₀ is lower alkyl.

Included within the scope of the invention are compounds of formula I wherein R 1 and R ₂ together represent = NR, wherein R 8 is R 10 O ₂ C-, R ₁₀ O-, cyano, R 10 CO-, optionally substituted lower alkyl, nitro or a group of formula Y ¹ Y ² N-. These derivatives may themselves comprise a biologically active compound useful for the treatment of a disease state which may be alleviated by inhibiting the production of factor Xa in a patient suffering from the disease state, or may serve as prodrugs of these biologically active compounds formed therefrom under physiological conditions.

The compounds of the invention are selected from the following:

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F

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The compounds of formula (I) may be prepared by the use or adaptation of known methods which are understood to mean the methods hitherto used or described in the literature or the methods of the invention.

Scheme A is an example of a general process for preparing intermediates for use in the preparation of compounds of Formula I of the invention.

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Scheme A o

0 0 Y ^ OMe ^NaOH ' ^THF ' Ify ^ OH temp. local.

CAN. CH 3 CN / THF then separation of the isomers

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Scheme B is an example of a general method for converting intermediates prepared according to Scheme A to compounds of Formula I of the invention.

Scheme B

Scheme C is an example of a general method for performing interconversions between the compounds of Formula I of the invention.

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Scheme C

1. HjS. Et 3 N pyridine

2. Mete

3. NH ₄ OAc, A

1. H ₂ S, Et ₃ N pyridine

2. Mete

3. NH ₄ OAc. Δ then NaBH ₄ iBuOCOCl. ETIN

COOH

1. AciO / pyridine / DMAP

2. HjS.EtjN pyridine

3. Méte

4. NH ₄ OAc, A

1. HCl / MeOH

NH ₄ OAc.A

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In addition, compounds of formula I wherein R ₃ is a hydroxymethyl group can be converted to the corresponding compounds with a thiolmethyl group by reaction with an alcohol and an alkyl or arylsulfonyl halide and displacing the alkyl or arylsulfonate with NaSH, then the thiolmethyl compounds can be alkylated or acylated, to obtain compounds in the field of the invention.

Scheme D is an example of a general method for converting a nitrile intermediate to a compound of formula I and other general methods for effecting interconversions between compounds of formula I according to the invention.

Scheme D

«

Scheme E is an example of another general method for performing interconversions between the compounds of Formula I of the invention.

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Scheme E

H ₂ . Pd / C. EtOH h ₂ n

COOMe

PSI

PSI

H ₂ . Pd / C. EtOH

TSD

COOMe

COOMe

Hin

scheme

general example

OMe for the preparation of compounds of formula I according to the invention wherein R ₄ represents optionally t-substituted phenethyl.

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Scheme F

BOQ

Scheme G is an example of a general process for the preparation of compounds of Formula I of this invention wherein R 4 is methyl.

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Scheme G

ps

NH O

TFA (where P = BOC)

H ₂ / CaCO ₃ (P = CBZ)

0 Aryl ^ N ’0 I JL NHo 0 ArylCOCI / Et3N or I K ArylCOOH / TBTU x OMe Ψ at CN CN

1) HCl / MeOH

2) NH 2 MeOH or

1) H 1 S, pyridine

2) Mel

3) NH _and OAc

ABOUT

One of ordinary skill in the art will recognize that certain compounds of Formula I may exhibit isomerism, e.g., geometric isomerism, e.g., isomerism E or Za optical isomerism, e.g., R or S configurations. Geometric isomers include the cis or trans forms of the alkenyl moieties of the compounds.

30997 / H of the invention. The individual geometric isomers and stereoisomers of Formula I and mixtures thereof are included within the scope of the invention.

These isomers may be separated from their mixtures by the use or adaptation of known methods, for example by chromatographic techniques and crystallization techniques, or may be prepared separately from the corresponding isomers or intermediates thereof, for example, by using or modifying the methods described herein.

The compounds of the invention are useful in the form of the free base or

an acid or a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.

When a compound of the invention is substituted with a basic moiety, acid addition salts are formed and are simply more suitable for use and, in practice, for use in the form of a salt containing an amount for use of the free base form. Acids that can be used to form acid addition salts preferably include those which, when combined with the free base, form pharmaceutically acceptable salts, i. salts whose anions are non-toxic to the patient in pharmaceutical doses of the salt, so that the beneficial inhibitory effects on factor Xa contained in the free base are not impaired by the side effects that can be attributed to anions. Although

the pharmaceutically acceptable salts of the basic compounds are preferred, all acid addition salts are useful as sources of the free base form, although the specific salt is only required as an intermediate, for example if the salt is formed for purification and identification purposes only or is used as an intermediate in pharmaceutically acceptable salts by ion exchange procedures.

Pharmaceutically acceptable salts in the field of the invention are derived from the following acids: mineral acids such as hydrochloric, sulfuric, phosphoric, and sulfamic acids and organic acids such as acetic, citric, lactic, tartaric, malonic, methanesulfonic, ethanesulfonic, benzenesulfonic, p. toluenesulfonic, cyclohexylsulfamic, quinine and the like. Corresponding acid addition salts include the following: hydrogenated halides such as hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates,

30997 / H citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-hydroxynaphthoates, gentisates, mesylates, methionates and di-p-toluoyltartrate methanesulfonates, benzenesulfonates, ethanesulfonates, ethanesulfonates and quinates, respectively.

According to a further aspect of the invention, the acid addition salts of the compounds of the invention are prepared by reacting the free base with the appropriate acid using or modifying known methods. For example, acid addition salts of the compounds of this invention are prepared by either dissolving the free base in an aqueous or aqueous-alcoholic solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution or reacting the free base and acid in an organic solvent. or may be obtained by evaporation of the solvent.

The acid addition salts of the compounds of this invention can be recovered from the salts using or modifying known methods. For example, the parent compounds of the invention can be recovered from their acid addition salts by reaction with a base, for example an aqueous solution of sodium bicarbonate or an aqueous solution of ammonia.

When the compound of the invention is substituted with an acid moiety, base addition salts may be formed, and are more suitable for use and, in practice, use of a salt form containing an amount for use of the free acid form. Bases which can be used to prepare base addition salts include preferably those which, in conjunction with the free acid, form pharmaceutically acceptable salts, i. salts whose cations are non-toxic to the body in pharmaceutical doses of salts, so that the beneficial inhibitory effects on factor Xa contained in the free base are not impaired by side effects that can be attributed to cations. Pharmaceutically acceptable salts in the field of the invention, including, for example, alkali metal and alkaline earth metal salts, are derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine , N-methylglycine, lysine, arginine, ornithine, choline, Ν, Ν'-dibenzylethylenediamine, chloroprocaine,

30997 / H diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide and the like.

The metal salts of the compounds of this invention can be obtained by reacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal with a free acid compound in an aqueous or organic solvent. The aqueous solvent used may be water or water mixed with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran or an ester such as ethyl acetate. These reactions are usually carried out at room temperature, but can be carried out under heating if desired.

The amine salts of the compounds of this invention can be obtained by reacting the amine with the free acid compound in an aqueous or organic solvent. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile or ketones such as acetone. The amino acid salts can be prepared in a similar manner.

The compounds of the present invention can be recovered from base addition salts using or modifying known methods. For example, the parent compounds of the invention can be recovered from their base addition salts by treatment with an acid, for example hydrochloric acid.

As will be understood by one of ordinary skill in the art, some of the compounds of this invention do not form stable salts. However, it is preferable to form acid addition salts from compounds of the invention having a heteroaryl group containing a nitrogen atom and / or from compounds containing an amino group as a substituent. Preferred acid addition salts of the compounds of this invention are those in which there is no labile acid group.

As the compounds of the invention themselves are useful as active ingredients, their salts are useful for the purification of the compounds, e.g.

30997 / H in the solubility of salts and parent compounds, by-products and / or starting materials by methods known to those skilled in the art.

The starting materials and intermediates are prepared by the use or adaptation of known methods, for example the methods described in the working examples, or obvious chemical analogues or methods of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention is further explained, but not limited to the following illustrative examples which illustrate the preparation of the compounds of the invention.

In the nuclear magnetic resonance (NMR) spectrum, chemical shifts are expressed in ppm relative to tetramethylsilane. The abbreviations have the following meanings: s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublets, dt = doublet of triplets, b = broad.

Example 1

Compound 1 e

. To a stirred solution of 20 g (153 mmol) of 3-cyanobenzaldehyde in 100 mL of cold tetrahydrofuran (THF) under nitrogen at room temperature was added 61.2 g (183 mmol) of methyl (triphenylphosphoranylidene) acetate. The mixture was allowed to stir at room temperature overnight and then evaporated in vacuo. The crude product was chromatographed (40% ethyl acetate / hexane) to give 27.3 g (96%) of acrylate 1.

¹ H NMR (CDCl ₃ , d): 7.43-7.8 (m, 5H), 6.47 (d, J = 12 Hz, 1H). 3.8 (s, 3 H).

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Example 2 Compound 2 ABOUT II cr OMe CN

To a stirred solution of 27.33 g of compound 1 in 150 mL of ethanol was added 2 g of 10% Pd / CaCO 3. The resulting mixture was hydrogenated for 8 hours at room temperature under 45 PSI of hydrogen on a Parr stirrer. The mixture was then filtered through a celite membrane and the filtrate evaporated in vacuo to give 26.93 g (98%) of compound 2 as a clear oil.

¹ H NMR (CDCl ₃ , d): 7.33-7.72 (m, 4H), 3.66 (s, 3H), 2.97 (t, J = 7.8 Hz, 2H), 2, 62 (t, J = 7.8Hz, 2H).

Example 3

Compound 3 •

To a stirred solution of compound 2 (16.8 g, 89 mmol) in 2: 1 tetrahydrofuran / methanol (200 mL) was added dropwise 9 N 10 N NaOH at room temperature. After 2 hours, most of the solvent was evaporated in vacuo and 30 mL of 5N HCl was added. The resulting mixture was extracted several times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered, and evaporated to give 9.8 g (63%) of pure acid 3 as a white solid.

¹ H NMR (CDCl 3, d): 7.35-7.55 (m, 4H), 2.98 (t, J = 7.9 Hz, 2H), 2.7 (t, J = 7.9 Hz) , 2H).

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Example 4

Compound 4 o

CN

To a stirred solution of 8.2 g (47 mmol) of carboxylic acid 3 in 0.5 mL of dimethylformamide (DMF) and cold CH ₂ Cl ₂ was added dropwise under nitrogen atmosphere at room temperature 6.1 mL (70 mmol) of oxalyl chloride. After 1 hour gas evolution ceased and the solvent and excess oxalyl chloride were removed in vacuo. The residue was redissolved in 100 mL cold CH ₂ Cl ₂ and cooled to 0 ° C. 5.6 g (50 mmol) of mercaptopyridine are added, followed by 7.9 ml (56 mmol) of triethylamine. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with CH ₂ Cl ₂ and washed with 1N NaOH. The organic layer was dried (MgSO4), filtered and evaporated. The residue was chromatographed (eluent 50% ethyl acetate / hexane) to give 5.12 g (84%) of thioester 4 as a yellow oil.

¹ H NMR (CDCl _3, d): 8.63 (d, J = 9 Hz, 1H), 7.7-7.8 (m, 1H), 7.27-7.62 (m, 6H),

3.05 (s, 4H).

Example 5

Compound 5

To a stirred solution of cinnamaldehyde (10.2 ml, 81 mmol) and p-anisidine (10 g, 81 mmol) in CH ₂ Cl ₂ (200 ml ₎ was added MgSO ₄ (19.55 g, 162 mmol) under nitrogen at 0 ° C. After 4 hours the mixture was filtered and

The 30997 / H filtrate was evaporated to give 18.87 g (98%) of imine compound 5 as a gold solid, not giving a solid.

¹ H NMR (CDCl ₃₁ d): 8.28 (m, 5 H), 7.52 (m, 2H), 7.38 (m, 2H), 7.2 (m, 2H), 7.12 (m 2H, 6.93 (m, 2H), 3.82 (s, 3H).

Example 6

Compound 6

To a stirred solution of 7 g (26 mmol) of thioester 5 in 120 mL of cold CH 2 Cl 2 was added 26.1 mL of a 1M solution of TClCl in CH 2 Cl 2 under a nitrogen atmosphere at -78 ° C. After 15 minutes, 3.6 ml (26 mmol) of triethylamine is added dropwise. The resulting mixture was allowed to stir for 0.5 h at -78 ° C and then a solution of 4.42 g (19 mmol) of imine 1 in 20 mL of CH 2 Cl 2 was added dropwise. The mixture was then warmed to 0 ° C. After 1.5 hours at this temperature, the mixture was quenched with saturated NaHCO 3 solution and partitioned with water. The organic layer was washed with 1N NaOH solution, dried (MgSO 4) and evaporated in vacuo. The crude product was chromatographed (eluent 40% ethyl acetate / hexane) to give 2.242 g (32%) of a 5: 1 mixture of trans- and cis-lactam 6a and 6b as a gum.

Major trans-isomer 6a ¹ H NMR (CDCl ₃ , d): 7.2-7.6 (m, 11H), 6.8 (d, J = 11Hz, 2H), 6.65 (d, J) = 15.8 Hz, 1H), 6.2 (dd, J = 15.8, 7.9 Hz, 1H), 4.32 (m, 1H), 3.72 (s, 3H), 3.00 -3.42 (m, 3H).

Example 7

Compound 7

30997 / H

To a stirred solution of 1.5 g (3.8 mmol) of 6a and 6b in 60 mL of a 1: 3 mixture of tetrahydrofuran and CH 3 CN was added a solution of 3.13 g (5.7 mmol) of ammonium cerium nitrate at -20 ° C. (CAN) in 10 ml of water. After 15 minutes an additional 1.5 g of CAN in 5 ml of water was added. After an additional 30 minutes, the mixture was quenched with saturated NaHCO 3 solution and allowed to reach room temperature. The resulting suspension was filtered through a celite membrane and washed several times with CH 2 Cl 2 in a total volume of 200 mL. The layers of the filtrate were separated and the organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product is chromatographed (eluent is 60% ethyl acetate / hexane) to give 476 mg (43%) of the pure trans-isomer of 7a together with 85 mg of a mixture of the cis-isomer of 7b and the trans-isomer of 7a.

Main trans-isomer of compound 7a ¹ H NMR (CDCl 3, d): 7.17-7.65 (m, 9H), 6.52 (d, J = 15.8 Hz, 1H), 6.25 (s, 1H),

6.14 (dd, J = 15.8, 7.9 Hz, 1H), 3.97 (m, 1H), 3.00-3.33 (m, 3H).

Compound minor isomer 7b ¹ H NMR (CDCl 3, d): 7.21-7.52 (m, 9H), 6.62 (d, J = 15.8 Hz, 1H), 6.45 (s, 1H),

6.1 (dd, J = 15.8, 7.9 Hz, 1H), 4.46 (m, 1H), 3.7 (m, 1H), 3.02-3.17 (m, 1H) , 2,8-

2.93 (m, 1H).

Example 8

Compound 8

30997 / H

To a stirred solution of trans-lactam 7a in cold CH 2 Cl 2 was added dropwise 4.04 ml (29 mmol) of triethylamine under a nitrogen atmosphere at room temperature. 5.05 g (23.2 mmol) of biphenylcarbonyl chloride are then added, followed by 50 mg of DMAP. After 30 minutes, the mixture was diluted with CH 2 Cl 2 and washed with 1N HCl solution. The organic layer was then dried over sodium sulfate, filtered and evaporated. The crude product was chromatographed (eluent was 30% ethyl acetate / hexane) to give 2.19 g (81%) of product 8 as a solid.

¹ H NMR (CDCl 3, d): 8.06 (m, 2H), 7.2-7.75 (m, 16H), 6.67 (d, J = 15.8 Hz, 1H), 6.23 (dd, J = 15.8, 7.9 Hz, 1H). 4.63 (m, 1H); 3.46 (m, 1H). 3.1-3.33 (m, 2 H).

Example 9

Compound 9

To a stirred solution of 2.19 g (4.7 mmol) of β-lactam 8 in 50 mL of tetrahydrofuran was added dropwise 13.6 mL of 1N NaOH solution at room temperature. After 2 hours, most of the tetrahydrofuran was removed in vacuo and 20 mL of 1N HCl solution was added. The resulting mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by reverse phase HPLC (CH 3 CN / water, 0.1% TFA (trifluoroacetic acid), gradient of 40-100) and the fractions containing the product were lyophilized to afford

1.1 g (50%) of carboxylic acid 9 as a white solid.

¹ H NMR (CDCl 3, d): 7.18-7.97 (m, 18H), 6.61 (d, J = 15.8 Hz, 1H), 6.2 (dd, J = 15.8) 7.9 Hz, 1H), 5.14 (m, 1H), 3.00-3.22 (m, 3H).

30997 / H

Example 10

Compound 10

To a stirred solution of 105 mg (0.22 mmol) of carboxylic acid 9 in 3 mL of cold methanol was added molecular sieve (about 50 mg). Hydrochloric acid was then bubbled through for 2 minutes. The mixture was allowed to stir overnight at room temperature and then evaporated under a nitrogen atmosphere. 3 ml of a 7N solution of ammonia in methanol are then added to the residue and the mixture is refluxed for 1.5 hours, allowed to cool and the solvent removed in vacuo. The residue was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA, gradient 40 to 100) and the fractions containing the product were lyophilized to afford 73 mg (53%) of product 10 as a white solid.

¹ H NMR (DMSO-d 6, d): 8.7 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 9 Hz, 2H), 7.78 (d, J = 9 Hz, 2H), 7.75-7.21 (m, 14H), 6.67 (d, J = 16.1 Hz, 1H), 6.4 (dd, J = 16.1, 7.8 Hz, 1H), 4.98 (dd, J = 16.1, 7.8 Hz, 1H), 3.46 (s, 3H), 3.25-3.18 (m, 1H), 3 , 05-2.88

(m, 2H).

Example 11

Compound 11

Pb

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with benzoyl chloride. The final product 11 was purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

30997 / H ¹ H NMR (methanol-d ₆ , d): 8.61 (d, J = 11.3 Hz, 1 H), 7.83 (d, J = 7.5 Hz, 2H), 7, 15-

7.67 (m, 14H). 6.67 (d, J = 15.8 Hz, 1H), 6.3 (dd, J = 15.8, 7.9 Hz, 1H), 4.98 (m, 1H), 3.55 ( s, 3H), 3.27 (m, 1H), 3.1 (m, 2H).

Example 12

Compound 12

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with o-toluoyl chloride. The final product 12 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.3 (s, 1H), 9.15 (s, 1H), 8.7 (d, J = 7.6 Hz, 1H), 7.7 (d J = 8Hz, 2H), 7.6 (d, J = 9Hz, 2H), 7.2-7.6 (m, 12H), 6.9 (d, J = 8Hz, 1H), 6.6 (d, J = 15Hz, 1H), 6.35 (dd, J = 15.6Hz, 1H), 4.9 (dd, J = 15.6Hz, 1H), 3.55 ( s, 3H),

3.2-3.3 (m, 1H); 2.8-3.0 (m, 1H); 2.3 (s, 3H).

T

Example 13

Compound 13

COOMe h ₂ n ^Ph

NH HN =

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with m-toluoyl chloride. The final product 13 is purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

30997 / H ¹ H NMR (DMSO-d 6, d): 9.3 (s, 1H), 9.2 (s, 1H), 8.7 (d, J = 7.6 Hz, 1H), 7.7 (d, J = 8Hz, 2H), 7.6 (d, J = 9Hz, 2H), 7.2-7.6 (m, 12H), 6.9 (d, J = 8) Hz, 1H). 6.6 (d, J = 15Hz, 1H), 6.35 (dd, J = 15.6Hz, 1H), 4.9 (dd, J = 16.6Hz, 1H), 3 1.6 (s, 3H),

3.2-3.3 (m, 1H); 2.8-3.0 (m, 1H); 2.35 (s, 3H).

Example 14

Compound 14

This compound is prepared in a similar manner to compound 10 above by removing Winter 5 and thioester 4. In the b-lactam acylation step, 4'-ethyl-4-biphenylcarbonyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 14 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.3 (s, 1H), 9.15 (s, 1H), 8.9 (d, J = 7.6 Hz, 1H), 8.2 (d J = 8Hz, 2H), 8.0 (d, J = 9Hz, 2H), 7.4-7.9 (m, 12H), 7.2 (d, J = 8Hz, 1H), 6.9 (d, J = 15 Hz, 1H), 6.6 (dd, J = 15.6 Hz, 1H), 5.2 (dd, J = 16.6 Hz, 1H), 3.7 ( s, 3H), 3,4-

3.5 (m, 1H); 3.1-3.2 (m, 1H); 2.85 (q, 2H); 1.4 (t, 3H).

Example 15

Compound 15

x

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with 3 ', 4'-dimethoxy-4-biphenylcarbonyl chloride.

30997 / H

The final product 15 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.5 (s, 1H), 9.3 (s, 1H), 8.9 (d, J = 7.6 Hz, 1H), 8.1 (d J = 8Hz, 2H), 7.9 (d, J = 9Hz, 2H), 7.8 (s, 2H), 7.4-7.7 (m, 11H), 7.25 ( d, J = 8 Hz, 1H), 6.6 (d, J = 15 Hz, 1H), 6.4 (dd, J = 15.6 Hz, 1H), 4.0 (s, 3H), 3.9 (s, 3H), 3.7 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.4 (m, 1H).

Example 16

Compound 16

This compound is prepared in a similar manner to compound 10 above by removing Winter 5 and thioester 4. In the β-lactam acylation step, 4- (2'-pyridyl) benzoyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 16 was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.5 (s, 1H), 9.3 (s, 1H), 8.9 (d, J = 7.6 Hz, 1H), 8.8 (s , 1H). 8.4 (d, J = 8Hz, 2H), 8.3 (d, J = 9Hz, 1H), 8.1 (d, J = 8Hz, 2H), 7.9 (s, 2H) 7.4-7.8 (m, 10H), 7.4 (d, J = 8Hz, 1H), 6.9 (d, J = 15Hz, 1H), 6.6 (dd, J = 15.6 Hz, 1H), 5.2 (dd, J = 16.6 Hz, 1H), 3.7 (s, 3H), 3.4-3.5 (m, 1H), 3.2 -3.4 (m, IH).

Example 17

Compound 17

30997 / H

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the β-lactam acylation step, 4- (3'-pyridyl) benzoyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 17 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.5 (s, 1H), 9.3 (s, 1H), 8.9 (d, J = 7.6 Hz, 1H), 8.5 (s) s, 1H), 8.2 (d, J = 8Hz, 2H), 8.1 (d, J = 9Hz, 2H), 7.9 (s, 2H), 7.4-7.8 ( m, 9H), 7.4 (d, J = 8Hz, 1H), 6.9 (d, J = 15Hz, 1H), 6.6 (dd, J = 15.6Hz, 1H) 5.2 (dd, J = 16.6 Hz, 1 H), 3.7 (s, 3 H), 3.4-3.5 (m, 1 H), 3.2-3.4 (m, 1 H) ).

•

Example 18

Compound 18

This compound is prepared in a similar manner to compound 10 above by removing winter 5 and thioester 4. In the β-lactam acylation step, 4- (4'-pyridyl) benzoyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 18 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized. ¹ H NMR (DMSO-d 6, d): 9.5 (s, 1H), 9.3 (s, 1H), 9.0 (d, J = 7.6 Hz, 1H), 8.2 (s 4H), 7.8 (s, 2H), 7.5-7.8 (m, 11H), 7.4 (d, J = 8Hz, 1H), 6.9 (d, J = 15) Hz, 1H), 6.6 (dd, J = 15.6 Hz, 1H), 5.2 (dd, J = 16.6 Hz, 1H), 3.7 (s, 3H). 3.4-3.5 (m, 1H);

3.4 (m, IH).

Example 19

Compound 19

30997 / H

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the β-lactam acylation step, 2'-methyl-4-biphenylcarbonyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 19 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized. ¹ H NMR (DMSO-d 6, d): 9.25 (s, 1H), 9.03 (s, 1H), 8.71 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 8Hz, 2H), 7.61 (d, J = 8Hz, 2H), 7.6-7.12 (m, 13H), 6.67 (d, J = 15.9Hz) , 1H). 6.42 (dd, J = 15.9, 7.8 Hz, 1H), 5.0 (dd, J = 16 Hz, 7.9 Hz, 1H), 3.32 (s, 3H),

3.3-3.15 (m, 1H); 3.11-2.9 (m, 2H); 2.21 (s, 3H).

Example 20

Compound 20

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 3'-methyl-4-biphenylcarbonyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 20 was purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d ₆ d): 9.25 (s, 1H), 8.99 (s, 1H), 8.68 (d, J = 8.7 Hz, 1H), 7.9 (d, J = 9Hz, 2H), 7.75 (d, J = 9Hz, 1H), 7.68-7.15 (m, 13H), 6.68 (d, J = 15.9Hz) (1H),

6.4 (dd, J = 15.9 Hz, 7.8 Hz, 1H), 5.0 (dd, J = 16 Hz, 7.9 Hz, 1H), 3.46 (s, 3H), 3 28-3.18 (m, 1H); 3.1-2.9 (m, 1H); 2.36 (s, 3H).

Example 21

Compound 21

30997 / H

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 3'-methyl-4-biphenylcarbonyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 21 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized. ¹ H NMR (DMSO-d 6, d): 9.25 (s, 1H), 8.99 (s, 1H), 8.68 (d, J = 8.7 Hz, 1H). 7.9 (d, J = 9Hz, 2H), 7.75 (d, J = 9Hz, 1H), 7.68-7.15 (m, 13H), 6.68 (d, J = 15) (9 Hz, 1H)

6.4 (dd, J = 15.9 Hz, 1 H), 5.0 (dd, J = 16.0, 7.9 Hz, 1 H), 3.46 (s, 3H), 3.28-3 18 (m, 1H); 3.1-2.9 (m, 1H); 2.36 (s, 3H).

Example 22

Compound 22

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4'-biphenylcarbonyl chloride is replaced with 3'-methoxy-4-biphenylcarbonyl chloride. The final product 22 was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (d 6 -DMSO-d 6): 9.23 (s, 1H), 8.96 (s, 1H), 8.69 (d, J = 8.7 Hz, 1H), 7.9 ( d.

J = 9.6 Hz, 2H), 7.68-7.18 (m, 12H), 6.96 (d, J = 9.6 Hz, 1H), 6.64 (d, J = 15.9) Hz,

1H), 6.39 (dd, J = 15.9, 7.8 Hz, 1H), 4.98 (dd, J = 16.0, 7.9 Hz, 1H), 3.81 (s , 3H),

3.47 (s, 3H), 3.28-3.17 (m, 1H), 3.08-2.86 (m, 2H).

30997 / H

Example 23

Compound 23

0 ^ 0

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with 2-naphthylcarbonyl chloride. The final product 23 was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.24 (s, 1H), 9.02 (s, 1H), 8.83 (d, J = 8.6 Hz, 1H), 8.4 (s 1 H, 8.08-7.85 (m, 4H), 7.68-7.2 (m, 12H), 6.68 (d, J = 15.8 Hz, 1H), 6.43 ( dd, J = 15.8, 7.8 Hz, 1H), 5.03 (dd, J = 15.8, 7.8 Hz, 1H), 3.46 (s, 3H), 3.28-3 2 (m, 1H); 3.13-2.95 (m, 2H).

Example 24

Compound 24

This compound was prepared in analogy to compound 10 above starting from imine 5 and thioester 4. In step b-lactam acylation is substituted for 4 biphenylcarbonyl chloride in 1 _{L-Naphthylcarbonyl.} The final product 24 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.27 (s, 1H), 9.11 (s, 1H), 8.88 (d, J = 8.67 Hz, 1H), 8.188.07 ( m, 1H), 8.05-7.9 (m, 2H), 7.7-7.2 (m, 13H), 6.73 (d, J = 15.9 Hz, 1H), 6.4 (dd, J = 15.9, 7.8 Hz, 1H), 5.07 (dd, J = 16.0, 7.9 Hz, 1H), 3.52 (s, 3H), 3.28 -3.17 (m, 1H); 3.12-2.95 (m, 2H).

30997 / H

Example 25

Compound 25

COOMe

H? N Ph

This compound was prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the β-lactam acylation step, 3'-ethyl-4-biphenylcarbonyl chloride was substituted for 4-biphenylcarbonyl chloride. The final product 25 was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.25 (s, 1H), 9.05 (s, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.88 (d J = 9 Hz, 2H), 7.76 (d, J = 9 Hz, 2H), 7.62 (m, 2H), 7.55-7.15 (m, 11H), 6.66 (d) J = 16 Hz, 1H), 6.4 (dd, J = 16.0, 7.8 Hz, 1H), 4.96 (dd, J = 16, 7.8 Hz, 1H), 3.47 (s, 3H), 3.3-3.18 (m, 1H), 3.1-2.88 (m, 2H), 2.67 (q, J = 8.5 Hz, 2H), 1, 22 (t, J = 8.5Hz, 3H).

Example 26

Compound 26

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the β-lactam acylation step, 4'-methoxy-4-biphenylcarbonyl chloride is substituted for 4-biphenylcarbonyl chloride.

The final product 26 was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

30997 / H ¹ H NMR (DMSO-d 6, d): 9.23 (s, 1H), 8.96 (s, 1H), 8.66 (d, J = 8.7 Hz, 1H), 7 88 (d, J = 9.1 Hz, 2H), 7.72-7.22 (m, 11H), 7.03 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 16.1 Hz, 1H), 6.4 (dd, J = 16.1, 7.9 Hz, 1H), 4.97 (dd, J = 16.1, 7.9 Hz, 1H), 3.77 (s, 3H), 3.46 (s, 3H), 3.28-3.15 (m, 1H), 3.08-2.88 (m, 2H).

Example 27

Compound 27

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with 2 ', 4'-dimethoxy-4-biphenylcarbonyl chloride. The final product 27 is purified by reverse phase HPLC (CH 3 CN: water, 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.23 (s, 1H), 9.07 (s, 1H), 8.63 (d, J = 9Hz, 1H), 7.81 (d, J) = 8.9 Hz, 2H), 7.68-7.15 (m, 13H), 6.72-6.52 (m, 1H), 6.45-6.3 (m, 1H), 5 , 04-

4.9 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.51 (s, 3H), 3.21-3.15 (m, 1H), 3 , 08-

2.85 (m, 2 H).

Example 28

Compound 28

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step,

30997 / H replaces 4-biphenylcarbonyl chloride with 2'-ethyl-4-biphenylcarbonyl chloride. The final product 28 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.25 (s, 1H), 8.92 (s, 1H), 8.69 (d, J = 8.7 Hz, 1H), 7.78 (d J = 9 Hz, 2H), 7.68-7.08 (m, 15H), 6.65 (d, J = 15.9 Hz, 1H), 6.38 (dd, J = 15.9,

7.8 Hz, 1H), 5.0 (dd, J = 16.0, 7.9 Hz, 1H), 3.46 (s, 3H), 3.28-3.18 (m, 1H), 2.52 (q, J = 9.6 Hz, 2H); 0.98 (t, J = 9.6 Hz, 3H).

Example 29

Compound 29

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4'-methyl-4-biphenylcarbonyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 29 is purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.22 (s, 1H), 8.91 (s, 1H), 8.68 (d, J = 8.7 Hz, 2H), 7.75 (d J = 9 Hz, 2H), 7.65-7.2 (m, 13H), 6.65 (d, J = 15.9 Hz, 1H), 6.39 (dd, J = 15.9) .

7.8 Hz, 1H), 4.99 (dd, J = 16.0, 7.9 Hz, 1H), 3.46 (s, 3H), 3.28-3.18 (m, 1H), 3.08-2.88 (m, 2H); 2.35 (s, 3H).

Example 30

Compound 30

30997 / H

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the β-lactam acylation step, 4'-biphenylcarbonyl chloride is replaced with 3'-ethoxy-4-biphenylcarbonyl chloride. The final product 30 is purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized. ¹ H NMR (DMSO-d 6, d): 9.22 (s, 1H), 9.05 (s, 1H), 8.7 (d, J = 8.7 Hz, 1H), 7.88 (d J = 9 Hz (2H), 7.76 (d, J = 9 Hz, 2H), 7.68-7.12 (m, 12H), 6.98-6.85 (m, 1H), 6 67 (d, J = 16Hz, 1H), 6.4 (dd, J = 16.0, 7.8Hz, 1H), 5.01 (dd, J = 16.0, 7.8Hz, 1H), 4.08 (q, J = 7.5Hz, 2H), 3.45 (s, 3H), 3.25-3.15 (m, 1H), 3.08-2.89 (m H, 1.32 (t, J = 7.5 Hz, 2H).

Example 31

Compound 31

COOMe

Ph _: Ph

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4'-ethoxy-4-biphenylcarbonyl chloride is substituted for 4-biphenylcarbonyl chloride. The final product 31 is purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.26 (s, 1H), 9.02 (s, 1H), 8.64 (d, J = 8.7 Hz, 1H), 7.86 (d J = 9Hz, 2H), 7.72 (d, J = 9Hz, 2H), 7.7-7.22 (m, T1H), 7.01 (d, J = 10.4Hz, 2H) 6.64 (d, J = 15.9 Hz, 1H), 6.38 (dd, J = 15.9, 7.8 Hz, 1H), 4.98 (dd, J = 16.0,

7.8 Hz, 1H), 4.06 (q, J = 8.2 Hz, 2H), 3.45 (s, 3H), 3.3-3.18 (m, 1H), 3.08- 2.85 (m, 2H), 1.32 (t, J = 8.2 Hz, 3H).

Example 32

Compound 32

30997 / H

This compound is prepared in a similar manner to compound 10 above by removing winterin 5 and thioester 4. In the b-lactam acylation step, 4'-biphenylcarbonyl chloride is replaced with 2'-ethoxy-4-biphenylcarbonyl chloride. The final product 32 is purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.24 (s, 1H), 9.11 (s, 1H), 8.68 (d, J = 8.7 Hz, 1H), 7.85 ( d, J = 9Hz, 2H), 7.6 (d, J = 9Hz, 2H), 7.59-6.95 (m, 13H), 6.65 (d, J = 15.9Hz,

H), 6.39 (dd, J = 15.9, 7.8 Hz, 1H), 4.98 (dd, J = 16.0, 7.8 Hz, 1H), 4.03 (q, J) = 8.1 Hz (2H), 3.47 (s, 3H), 3.28-3.18 (m, 1H), 3.1-2.88 (m, 2H), 1.24 (t , J = 8.1 Hz,

3H).

Example 33

Compound 33

To a stirred solution of 2-naphthaldehyde (20 g, 0.13 mol) in CH 2 Cl 2 (200 mL) was added p-anisidine (15.8 g, 0.13 mol) followed by anhydrous sulfate (16.9 g, 0.14 mol). magnesium. After 3.5 hours, the mixture was filtered and the filtrate evaporated in vacuo to give 31.5 g (92) of imine 33.

¹ H NMR (CDCl 3, d): 8.64 (s, 1H), 8.19 (m, 2H), 7.78-7.98 (m, 3H), 7.43-7.56 (m, 2H), 7.32 (m, 2H), 6.96 (m, 2H), 3.83 (s, 3H).

Example 34

Compound 34

30997 / H

Prepared as described above for compound 33 using trans-3- (2'-naphthyl) acrolein, β-anisidine and anhydrous magnesium sulfate.

¹ H NMR (CDCl ₃ , d): 8.35 (d, J = 9Hz, 1H), 7.78-7.9 (m, 4H), 7.72 (m, 1H), 7.5 ( m, 2H), 7.25 (m, 4H), 6.93 (m, 2H), 3.82 (s, 3H).

Example 35

Compound 35

Prepared as described above for compound 33 using trans-3- (4'-biphenyl) acrolein, p-anisidine, and anhydrous magnesium sulfate. ¹ H NMR (CDCl 3, d): 8.33 (d, J = 9 Hz, 1H), 7.2-7.68 (m, 13H), 6.9 (m, 2H), 3.82 ( s, 3H).

Example 36

Compound 36

Prepared as described above for compound 33 using 4-biphenylcarboxaldehyde, p-anisidine and anhydrous magnesium sulfate.

30997 / H ¹ H NMR (CDCl 3, d): 8.52 (s, 1H), 7.97 (m, 2H), 7.62-7.73 (m, 4H), 7.35-7.52 (m, 3H), 7.27 (m, 2H), 6.95 (m, 2H), 3.85 (s, 3H).

Example 37

Compound 37

This compound is prepared in a similar manner to compound 10 above by removing from imine 33 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with benzoyl chloride. The final product 37 was purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (methanol-d ₄ , d): 9.01 (d, J = 9.4 Hz, 1H), 7.77-7.98 (m, 6H), 7.43-7.67 ( m, 9H), 5.53 (m, 1H), 3.56 (m, 1H), 3.54 (s, 3H), 3.1 (m, 1H), 2.81 (m, 1H).

Example 38

Compound 38

This compound is prepared in a similar manner to compound 10 above by removing from imine 34 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with benzoyl chloride. The final product 38 is purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d 6, d): 9.27 (s, 2H), 9.1 (s, 2H), 8.72 (d, 1H), 7.4-7.95 (m, 16H) 6.86 (d, J = 18Hz, 1H), 6.54 (dd, J = 10.6Hz, 1H), 5.03 (m, 1H), 3.48 (s, 3H), 3 32 (m, 1 H), 3.04 (m, 2 H).

30997 / H

Example 39

Compound 39

This compound is prepared in a similar manner to compound 10 above by removing from imine 35 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with benzoyl chloride. The final product 39 is purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA) and lyophilized.

1 H NMR (DMSO-d 6, d): 9.25 (s, 2H), 9.11 (s, 2H), 8.74 (d, 1H), 7.30-8.0 (m, 22H) 6.23 (d, J = 18Hz, 1H), 6.47 (dd, J = 18.6Hz, 1H), 5.04 (m, 1H), 3.49 (s, 3H), 3 3 (m, 1H); 3.03 (m, 2H).

Example 40

Compound 40

This compound is prepared in a similar manner to compound 10 above by removing from imine 36 and thioester 4. In the b-lactam acylation step, 4-biphenylcarbonyl chloride is replaced with benzoyl chloride. The final product 40 is purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA) and lyophilized.

¹ H NMR (DMSO-d ₆ , d): 9.23 (s, 2H), 9.05 (s, 2H), 8.97 (s, 2H), 7.28-7.8 (m,

18H), 5.35 (t, 1H), 3.42 (s, 3H), 3.31 (m, 1H), 2.89 (dd, 1H), 2.6 (dd, 1H).

30997 / H

Example 41

Compound 41

To a stirred solution of 980 mg (2 mmol) of carboxylic acid 9 and 0.44 ml (3.2 mmol) of triethylamine in cold tetrahydrofuran was added dropwise 0.39 ml (3 mmol) of isobutyl chloroformate under nitrogen at 0 ° C. After 15 minutes, a solution of 153 mg (4 mmol) of sodium borohydride in 5 mL of water was added dropwise. The mixture was allowed to warm to room temperature. After 1 hour, most of the tetrahydrofuran was evaporated in vacuo. Water was then added and the mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO 4), filtered and evaporated. The crude product is purified by chromatography (eluent is 35% ethyl acetate: hexane) to give 720 mg (76%) of alcohol 41.

¹ H NMR (CDCl 3, d): 7.92 (d, J = 9Hz, 1H), 7.2-7.72 (m, 16H), 6.67 (d, J = 15.5Hz, 1 H); H), 6.27 (dd, J = 15.5, 7.8 Hz, 1H), 4.94 (m, 1H), 3.88 (m, 1H), 3.5 (m, 1H) 3.12 (m, 1H); 2.82-3.03 (m, 2H); 1.95 (m, 1H).

® Example 42

Compound 42

To a stirred solution of 106 mg (0.22 mmol) of alcohol 41 in 3 mL of cold methanol was added molecular sieve (about 50 mg) at room temperature. Hydrochloric acid was then bubbled through for 2 minutes. The mixture was then allowed to stir at room temperature overnight and then evaporated under a stream of nitrogen. 3 ml of 7N ammonia solution are then added to the residue

30997 / H in methanol and the mixture was allowed to reflux for 3.5 hours, allowed to cool and the solvent evaporated in vacuo. The residue was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA, gradient, 40 to 100) and the product containing fractions were lyophilized to afford 29 mg (22%) of product 42 as the trifluoroacetate salt.

Example 43

Compound 43

To a stirred solution of 88 mg (0.2 mmol) of the alcoholic compound in 2 mL of a 2: 1 mixture of tetrahydrofuran and dimethylformamide was added 15 mg (0.4 mmol) of a 60% sodium hydride dispersion under nitrogen at 0 ° C. After 15 minutes, methyl iodide (0.02 mL, 0.3 mmol) was added and the mixture was allowed to warm to room temperature. After 2 hours, quench the mixture with saturated sodium bicarbonate solution. Most of the tetrahydrofuran was evaporated in vacuo and the residue was diluted with water and extracted with CH 2 Cl 2. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crude product is chromatographed (eluent is 35% ethyl acetate: hexane) to give 21 mg (23%) of product 43 along with 34 mg of recovered alcohol 41.

¹ H NMR (CDCl 3, d): 7.93 (d, J = 9.3 Hz, 2H), 7.15-7.83 (m, 16H), 6.57 (d, J = 15.8 Hz) 1 H), 6.22 (dd, J = 15.8, 6.8 Hz, 1H), 5.0 (m, 1H), 3.75 (m, 1H), 3.42 (s, 3H) 3.27 (m, 1H), 2.87-3.03 (m, 2H), 2.12 (m, 1H).

Example 44

Compound 44

30997 / H

To a stirred solution of 20 mg (0.04 mmol) of compound 43 in 1.5 mL of a 2: 1 mixture of pyridine and triethylamine was bubbled hydrogen sulfide for approximately 1 minute. The mixture was allowed to stir at room temperature overnight and then evaporated under a stream of nitrogen and then taken up in 2 ml of dichloromethane. 1 ml of methyl iodide was added and the mixture was heated under reflux for 1 hour. The solvent is evaporated in vacuo, the residue is taken up in 2 ml of methanol and then 30 mg of ammonium acetate are added. The resulting mixture was refluxed for 1 hour and then allowed to cool. The solvent was then evaporated in vacuo and the residue was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA, gradient of 40-100% CH 3 CN) and the product containing fractions were lyophilized to afford 13 mg (51%) of 44 as trifluoroacetate. salt.

¹ H NMR (methanol-d ₄ , d): 8.47 (d, J = 7.9 Hz, 1 H), 7.95 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.17-7.73 (m, 14H), 6.55 (d, J = 15.8 Hz, 1H), 6.31 (dd, J = 15.8, 7, 9 Hz, 1H), 4.77 (m, 1H), 3.7 (dd, J = 9.5, 3.1 Hz, 1H), 3.47 (dd, J = 9.5, 3.1) Hz, 1H), 3.00 (d, J = 7.9 Hz, 2H), 2.35 (m, 1H).

Example 45

Compound 45

A mixture of 480 mg (1 mmol) of alcohol 41, 0.40 mL (4.9 mmol) of pyridine and

0.12 ml (1.2 mmol) of acetic anhydride is stirred at room temperature overnight. The next day, 3 drops of pyridine and acetic anhydride are added. The next day the reaction is not complete, so 4 mg of DMAP is added. After 1 hour the reaction was complete.

The mixture was diluted with dichloromethane and washed with 0.1 N hydrochloric acid.

30997 / H

The organic layer was dried over magnesium sulfate, filtered, and evaporated to give 520 mg of 45.

¹ H NMR (CDCl ₃ , d): 7.98 (d, J = 8Hz, 1H), 7.73 (d, J = 8Hz, 2H), 7.67 (d, J = 8Hz, 2H), 7.17-7.58 (m, 12H), 6.94 (d, 1H), 6.55 (d, J = 18Hz, 1H), 6.21 (dd, J = 18, 5) Hz, 1H), 5.1 (m, 1H), 4.38 (m, 1H), 4.08 (m, 1H), 2.68-2.97 (m, 2H), 2.51 (m , 1H).

Example 46

Compound 46

Compound 45 is converted to the corresponding amidine 46 using the hydrogen sulfide / methyl iodide / ammonium acetate sequence described for conversion 43 to 44. The product 46 is purified by reverse-phase HPLC and isolated as the trifluoroacetate salt.

¹ H NMR (DMSO-d 6, d): 9.31 (s, 2H), 8.97 (s, 1H), 8.7 (d, 1H), 7.18-8.00 (m, 18H) 6.6 (d, J = 18Hz, 1H), 6.40 (dd, J = 18.6Hz, 1H), 4.83 (m, 1H), 4.02 (m, 1H), 3.84 (m, 2H), 2.95 (m, 1H), 2.57 (m, 1H), 1.93 (s, 3H).

Example 47

Compound 47

COOH ^H 2 ^N Ph

The carboxylic acid 9 is converted to the corresponding amidine 47 using the hydrogen sulfide / methyl iodide / ammonium acetate order described for the conversion

30997 / H at 44. The product 47 is purified by reverse-phase HPLC and isolated as the trifluoroacetate salt.

¹ H NMR (methanol-d ₄₁ d): 8.00 (d, J = 9 Hz, 2H), 7.82 (d, J = 9 Hz, 2H). 7.22-7.77 (m, 14H), 6.73 (d, J = 15.8 Hz, 1H), 6.4 (dd, J = 15.8, 7.9 Hz) 7 (m, 14H), 6.73 (d, J = 15.8 Hz, 1H), 6.4 (dd, J = 15.8, 7.9 Hz, 1H), 4.95 (m, 1H), 3, 08-3.45 (m. 3H).

Example 49

Compound 49

COOlPr

N _C

To a stirred solution of 120 mg (0.29 mmol) of carboxylic acid 48 in 5 mL of cold dichloromethane under nitrogen at room temperature was added 0.05 mL (0.38 mmol) of triethylamine and dropwise 0.38 mL of a 1 M solution of isopropyl chloroformate in toluene. After 30 minutes, DMAP (18 mg, 0.15 mmol) was added and the mixture was allowed to stir at room temperature for 1.5 hours. The mixture was then diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was then dried over magnesium sulfate, filtered, and evaporated. The crude product is chromatographed (eluent 40% ethyl acetate: hexane) to give 44 mg (33%) of the corresponding isopropyl ester. This compound is then converted to the corresponding amidine 49 in the manner described for converting 43 to 44 in the order of hydrogen sulfide / methyl iodide / ammonium acetate. The product 49 is purified by reverse-phase HPLC and isolated as the trifluoroacetate salt.

¹ H NMR (methanol-d ₄ , d): 8.6 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8 Hz, 2H). 7.16-7.7 (m, 12H), 6.69 (d, J = 15.8 Hz, 1H), 6.32 (dd, J = 15.8, 7.9 Hz, 1H), 4 98 (m, 1 H),

4.85 (m, 1H), 3.23 (m, 1H), 3.08 (m, 2H), 1.07 (d, J = 6Hz, 3H), 0.97 (d, J = 6) Hz, 3H).

30997 / H

Example 50 Compound 50 COOiPr H, N Pb NH HN =

This compound was prepared by converting 48 to the corresponding amidine using the hydrogen sulfide / methyl iodide / ammonium acetate sequence described for conversion 43 to 44. The product 50 was purified by reverse-phase HPLC and isolated as the trifluoroacetate salt.

¹ H NMR (methanol-d ₄ , d): 8.6 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8 Hz, 2H), 7.16-7.7 ( m, 12H), 6.69 (d, J = 15.8 Hz, 1H), 6.32 (dd, J = 15.8, 7.9 Hz, 1H), 4.98 (m, 1H )

4.85 (m, 1H), 3.23 (m, 1H), 3.08 (m, 2H), 1.07 (d, J = 6Hz, 3H), 0.97 (d, J) = 6 Hz, 3H).

Example 51

Compound 51

Hydrochloric acid was bubbled into the stirred solution of 96 mg (0.18 mmol) of carboxylic acid 50 in 3 mL of ethanol at room temperature for 3 minutes. The mixture was allowed to stir at room temperature for 7 hours and then stored in a refrigerator over the weekend. The solvent was then evaporated in vacuo and the residue purified by reverse phase HPLC. The product 51 is isolated as its trifluoroacetate salt.

¹ H NMR (methanol-d ₄ , d): 8.63 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8 Hz, 2H), 7.16-7.68 ( m, 12H), 6.68 (d, J = 15.8 Hz, 1H), 6.32 (dd, J = 15.8, 7.9 Hz, 1H), 5.00 (m, 1H), 4.02 (q, 2H), 3.25 (m, 1H), 3.07 (d, J = 7.9 Hz, 2H), 1.05 (t, 3H).

30997 / H

Example 52

Compound 52

COOMe

The mixture of compound and 25 mg of 10% palladium on carbon was hydrogenated under 45 psi H 2 in a mixture of 2 mL of ethyl acetate and 5 mL of ethanol at room temperature for 19 hours. The mixture was then filtered through a pad of celite and the filtrate was evaporated. The crude product was purified by reverse phase HPLC (CH ₃ CN: water: 0.1% TFA, CH ₃ CN gradient 10 to 100%) and the product containing fractions were lyophilized to give 21 mg of 52.

¹ H NMR (methanol-d ₄ , d): 8.27 (d, J = 9.3 Hz, 1H), 7.83 (m, 2H), 7.43-7.65 (m, 7H), 7.09-7.27 (m, 5H), 4.35 (m, 1H), 3.58 (s, 3H), 2.95-3.15 (m, 3H), 2.54-2, 75 (m, 2H); 1.93 (m, 2H).

Cleavage of compound 10

The racemic mixture of compound 10 (ca. 650 mg, single diastereoisomer with presumed common stereochemistry shown) was resolved into its two enantiomers 53 (later eluted isomer) and 54 (former eluted isomer) using preparative HPLC (Chiralpak AD column, 50 mm ID x 500 mm) , 15 μπι). The mobile phase is heptane (A) with 0.1% TFA and isopropanol (B) with 0.1% TFA, isocratic elution 20% A, 80% B (flow rate 200 ml / min). The later eluted isomer is isolated by evaporation in vacuo. Yield: 180 mg. Enantiomer 53 was detected by 100% analytical HPLC (Chiralpak AD). ¹ H NMR spectra are identical for 53 and 54. ¹ H NMR (DMSO-d ₆ , d): 8.7 (d, J = 8.6Hz, 1H), 7.92 (d, J = 9Hz, 2H), 7.78 (d, J = 9 Hz, 2H), 7.75-7.21 (m, 14H), 6.67 (d, J = 16.1 Hz, 1H), 6.40 (dd, J = 16.1, 7.8 Hz, 1H), 4.98 (dd, J = 16.1, 7.8 Hz, 1H), 3.46 (s, 3H), 3.25-3.18 (m, 1H), 3.05 -2.88 (m, 2 H).

30997 / H

Example 55

Compound 55

Hydrogenation of compound 53 (the later eluting enantiomer) was carried out as described above for compound 52 except that ethyl acetate was omitted. The product was purified by reverse phase HPLC (CH 3 CN: water: 0.1% TFA, gradient 40 to 100% CH 3 CN) and the product 55 was isolated as the trifluoroacetate salt.

¹ H NMR (methanol-d ₄ , d): 8.3 (d, J = 9.3 Hz, 1H), 7.84 (m, 2H), 7.07-7.8 (m, 16H), 4.37 (m, 1H), 3.6 (s, 3H), 2.97-3.17 (m, 3H), 2.57-2.77 (m, 2H), 1.95 (m , 2H).

Example 56

Compound 56

N Boe

COOCH

To a solution of 38 mmol of Ν-α-Boc-D-phenylalanine in 80 mL of cold tetrahydrofuran at -20 ° C was added in one portion 38 mmol of N-methylmorpholine, followed in a similar manner by 38 mmol of isobutyl chloroformate. The reaction mixture is stirred for 10 minutes at -20 ° C and filtered at 0 ° C into the prepared ethereal solution of 70 mmol of diazomethane. The resulting solution was allowed to stand at 0 pri C for 20 minutes. Excess diazomethane was quenched by the dropwise addition of glacial acetic acid and the solvents were evaporated in vacuo.

30997 / H

The resulting oil was dissolved in 150 mL cold methanol. A solution of 8 mmol of silver benzoate in 17 ml of triethylamine is slowly added with stirring at room temperature. The resulting black reaction mixture was stirred at room temperature for 45 minutes. The methanol is removed in vacuo and the residue is taken up in 700 ml of ethyl acetate. The mixture was filtered through celite and washed successively with saturated sodium bicarbonate (3 x 150 mL), once with water (1 N, potassium sulfate (3 x 150 mL) and brine). The organic layer was dried over magnesium sulfate, filtered, evaporated in vacuo and purified by flash chromatography (hexanes: ethyl acetate 3: 1).

Example 57

Compound 57

NHSoc / k → COOCH

Compound 57 was prepared using the procedure described for Compound 56, substituting N-α-Boc-D-alanine.

Example 58

Compound 58

NHBoc

I _FROM COOCH ₃

Compound 58 was prepared using the procedure described for Compound 56, substituting N-α-Boc-D-homophenylalanine.

Example 59

Compound 59

30997 / H

NHBoc

N <Jkxk / ^C00CH3

Compound 59 was prepared using the procedure described for Compound 56, substituting N-α-Boc-D-3-pyridylalanine.

Example 60

Compound 60

NHBoc

COOCH ₃

Compound 60 was prepared using the procedure described for Compound 56, substituting N- -Boc-D-isoleucine.

Example 61

Compound 61

NHBoc

UxA / ^C00CH 3

Compound 61 was prepared using the procedure described for Compound 56, substituting N-α-Boc-D-cyclohexylalanine.

Example 62

Compound 62

30997 / H

WITH&-'-?·.··.·

• 7 / ΐ

i <eat her

A solution of 11 mmol of compound 56 in 70 mL of cold tetrahydrofuran was cooled to -78 ° C and a solution of 33 mmol of hexamethyldisilazane in tetrahydrofuran was added via syringe at a rate such that the temperature did not exceed -60 ° C. The reaction mixture was warmed to -25 ° C over 40 minutes and recooled to -78 ° C. A solution of 27 mmol of 3-cyanobenzyl bromide in 20 mL of tetrahydrofuran is added via syringe at a rate such that the temperature does not exceed -60 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature.

5 ml of saturated sodium bicarbonate solution were added and the tetrahydrofuran was evaporated in vacuo. The residue was partitioned between ethyl acetate (500 mL) and saturated sodium bicarbonate (150 mL). The organic phase is further washed twice with 100 ml of saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was triturated with 40 mL of 4: 1 hexanes / ethyl acetate. The solid was filtered and discarded. The filtrate containing the desired product is evaporated in vacuo.

Example 63

Compound 63 NHBoc /L.COOCH3 \ · vi . CN

Compound 63 was prepared according to the procedure described for Compound 62, substituting the product obtained in Example 57.

30997 / H

Example 64

Compound 64

Compound 64 was prepared according to the procedure described for Compound 62, substituting the product obtained in Example 58.

Example 65

Compound 65

Compound 65 was prepared according to the procedure described for Compound 62, substituting the product obtained in Example 59.

Example 66

Compound 66

Compound 66 was prepared according to the procedure described for Compound 62, substituting the product obtained in Example 60.

30997 / H

Example 67

Compound 67

Compound 67 was prepared according to the procedure described for Compound 62, substituting the product obtained in Example 61

Example 68

Compound 68

To a solution of 5 mmol of compound 62 in 60 mL of methylene chloride was added 20 mL of trifluoroacetic acid dropwise at 0 ° C. The resulting solution was stirred at 0 ° C for 2 hours. The solvents were removed in vacuo and the residue was purified by reverse phase HPLC using a gradient of 30% to 70% acetonitrile in water containing 0.1% trifluoroacetic acid.

The acetonitrile was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo.

Example 69

Compound 69

30997 / H

Compound 69 was prepared according to the procedure described for Compound 68, substituting the product obtained in Example 63.

Example 70

Compound 70

Compound 70 was prepared according to the procedure described for Compound 68, substituting the product obtained in Example 64.

Example 71

Compound 71

Compound 71 was prepared according to the procedure described for Compound 68, substituting the product obtained in Example 65.

Example 72

Compound 72

30997 / H

Compound 72 was prepared according to the procedure described for Compound 68, substituting the product obtained in Example 66.

Example 73

Compound 73

Compound 73 was prepared according to the procedure described for Compound 68, substituting the product obtained in Example 67.

Example 74

Compound 74

F ^ -cooch

Solution A ·

To a solution of 11.8 ml (19 mmol) norm. butyllithium in hexanes in 13 ml of tetrahydrofuran at -78 ° C is added dropwise via syringe a solution of 19 mmol of 1-bromo-2-fluorobenzene in 2 ml of tetrahydrofuran. Mixing at

-78 ° C continued for 1 hour. After 2 minutes a solution of 19 mmol was added at -78 ° C

30997 / H zinc chloride in 38 ml tetrahydrofuran. The resulting solution was allowed to warm to room temperature over 40 minutes.

Solution B

To a solution of 1 mmol of bis (triphenylphosphine) palladium dichloride in 11 mL of tetrahydrofuran at room temperature was added a solution of 1 mmol of diisobutyl aluminum hydride in hexanes, followed by addition of 16 mmol of methyl iodo benzoate at room temperature in one portion.

Solution A was added to solution B and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with 300 mL of diethyl ether and washed three times with 75 mL of 1N hydrochloric acid and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo.

Example 75

Compound 75

Compound 75 was prepared as described for Compound 74, substituting 1-bromo-3-fluorobenzene for the preparation of Solution A.

K \

Example 76

Compound 76 ^f <H> ^{coocH 3}

30997 / H

Compound 76 was prepared according to the procedure described for Compound 74, substituting 1-bromo-4-fluorobenzene in the preparation of Solution A.

Example 77

Compound 77

COOCH ₃

Compound 77 was prepared as described in Example 74, substituting 3,4-ethylenedioxy bromobenzene for the preparation of solution A.

Example 78

Compound 78

\ ^ -cooch ₃

Compound 78 was prepared as described in Example 74, substituting 3,4-methylenedioxy bromobenzene for solution A.

Example 79 x

Compound 79

COOCH

Compound 79 was prepared as described in Example 74, substituting 3,4-dimethoxy bromobenzene for the preparation of Solution A.

30997 / H

Example 80

Compound 80

Compound 80 was prepared as described in Example 74, substituting 3-cyanobromobenzene for the preparation of Solution A.

Example 81

Compound 81

Ammonia was bubbled into a suspension of 24 mmol of compound 80 in 200 mL of methanol for 5 minutes. To the resulting solution was added 5 g of aluminum on aluminum, and the suspension was shaken under direct hydrogen pressure for 36 hours. The catalyst was filtered off and the methanol was removed in vacuo to give an oil which was triturated with ether and filtered off.

Example 82

Compound 82

BocNH

COÔCH ₃

30997 / H

A solution of 15.4 mmol of 81.17 mmol of triethylamine, 15.4 mmol of tert-dibutyl dicarbonate and 1.5 mmol of 4-dimethylaminopyridine in 60 mL of DMF was stirred overnight at room temperature. The solution was diluted with 800 mL of ethyl acetate and washed three times with 150 mL of 1N hydrochloric acid and brine. The organic layer was dried over magnesium sulfate, filtered, evaporated in vacuo and purified by flash chromatography (hexanes: ethyl acetate 3: 2).

Example 83

Compound 83

AcNH

cooch ₃

A solution of 2 mmol of compound 81, 8 mmol of acetic anhydride and 0.2 mmol of dimethylaminopyridine in 20 mL of pyridine was stirred overnight at room temperature. The reaction mixture is poured into 200 ml of 5% hydrochloric acid and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered, evaporated in vacuo and purified by flash chromatography (hexanes: ethyl acetate 3: 1).

Example 84

Compound 84 ^NC YT 1 / ^{COOCH 3}

Compound 84 was prepared as described for Compound 74, substituting 4-cyanobromobenzene for the preparation of Solution A.

30997 / H

Example 85

Compound 85

Compound 85 was prepared according to the procedure described for Compound 81, substituting the product obtained in Example 84.

Example 86

Compound 86 ^BOCHN- O-Coch ₃

Compound 86 was prepared according to the procedure described for Compound 82, substituting the product obtained in Example 85.

Example 87

Compound 87

AcHN

COOCH ₃

Compound 87 was prepared according to the procedure described for Compound 83, substituting the product for Example 85.

30997 / H

Example 88

Compound 88 cooch ₃ o ₂ n

To a solution of 6.5 mmol of methylcoumalate and 32.5 mmol of 3-nitrostyrene in 30 mL of m-xylene was added 2.5 g of 10% palladium on carbon in one portion. The reaction mixture was heated at 140 ° C overnight. After cooling, the reaction mixture was filtered through celite and the filtrate was evaporated in vacuo. The resulting suspension was triturated with 3: 1 hexanes / triethyl acetate. The solid which is the desired product is removed by filtration.

Example 89

Compound 89

Ο ^-

Cooch

Compound 89 was prepared in a manner similar to compound 88, substituting 4-nitrostyrene.

Example 90

Compound 90

30997 / H

To a flask containing 100 ml of fuming nitric acid, 20 mmol of 4-biphenylcarboxylic acid is added portionwise at 0 ° C. Stirring at 0 ° C was continued for 15 minutes. Water (100 ml) was added slowly and the filtrate was combined and recrystallized from ethanol.

Example 91

Compound 91

COOCH ₃

Compound 91 was prepared according to the procedure described for Compound 74, substituting 3-benzyloxy bromobenzene for the preparation of Solution A.

Example 92

Compound 92

Compound 92 was prepared as described for Compound 74, substituting 4-benzyloxy bromobenzene for the preparation of Solution A.

Example 93

Compound 93

F

COOH

30997 / H

To a suspension of 1.6 mmol of 74 in 10 mL of methanol and 20 mL of tetrahydrofuran was added dropwise 10 mL of 2N sodium hydroxide at room temperature. The resulting solution was allowed to stir at room temperature for 2 hours. The organic solvents are removed in vacuo and the residue is diluted with 20 ml of water and adjusted to pH 2 with 1N hydrochloric acid. The solid is filtered off and dried in vacuo.

Example 94

Compound 94

θ-θ- ^ΟΟΟΗ

F ^{/ _}

Compound 94 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 75.

Example 95

Compound 95

COOH. Compound 95 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 76.

Example 96

Compound 96

COOH

30997 / H

Compound 96 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 77.

Example 97

Compound 97

COOH

Compound 97 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 78.

Example 98

Compound 98

COOH

Compound 98 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 79.

Example 99

Compound 99

BocHN

30997 / H

Compound 99 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 82.

Example 100

Compound 100

AcHN

COOH

Compound 100 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 83.

Example 101

Compound 101

BocHN

COOH

Compound 101 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 86.

Example 102

Compound 102

AcHN

COOH

30997 / H

Compound 102 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 87.

Example 103

Compound 103 o ₂ n

COOH

Compound 103 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 88.

Example 104

Compound 104 ° ²ⁿ ^ 0 ⁼ 7 ° ^{C oh}

Compound 104 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 89.

Example 105

Compound 105

30997 / H

Compound 105 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 91.

Example 106

Compound 106 ABOUT l - - ° 0 ~ 0 “ ^cooh

Compound 106 was prepared according to the procedure described for Compound 93, substituting the product obtained in Example 90.

Example 107

Compound 107

To a solution of 2 mmol of compound 96 in 10 mL of dimethylformamide was added 2 mmol of diisopropylethylamine at room temperature at once, followed by 2 mmol of 2- (1H-1-benzotriazolyl) -1,1,3 _L 3-tetramethyluronium tetrafluoroborate in a similar manner. The reaction mixture was stirred at room temperature for 2 minutes and

30997 / H were added at room temperature 2 mmol of 70 in 15 mL of DMF. Stirring is continued overnight at room temperature.

The reaction mixture is diluted with 300 ml of ethyl acetate and washed successively with 3 times 75 ml of 1N hydrochloric acid, water, 3 times with 75 ml of sodium bicarbonate and brine. The organic phase is dried over magnesium sulphate, filtered and evaporated in vacuo.

Example 108

Compound 108

Compound 108 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 93.

Example 109

Compound 109

Compound 109 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 94.

30997 / H

Example 110

Compound 110

Compound 110 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 95.

Example 111

Compound 111

Compound 111 was prepared using the same procedure as described for compound 107, substituting 4-biphenylcarboxylic acid for compound 96 and 68 for compound 70.

30997 / H

Example 112

Compound 112

Compound 112 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 97.

Example 113

Compound 113

Compound 113 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 98.

30997 / H

Example 114

Compound 114

Compound 114 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 99 and replacing compound 70 with compound 68.

Example 115

Compound 115

Compound 115 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 100 and replacing compound 70 with compound 68.

30997 / H

Príklad116

Compound 116

Compound 116 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 101 and replacing compound 70 with compound 68.

Example 117

Compound 117

Compound 117 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 102 and replacing compound 70 with compound 68.

30997 / H

Example 118

Compound 118

Compound 118 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 103 and replacing compound 70 with compound 68.

Example 119

Compound 119

Compound 119 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 104 and replacing compound 70 with compound 68.

30997 / H

Example 120

Compound 120

Compound 120 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 90 and replacing compound 70 with compound 68.

Example 121

Compound 121

Compound 121 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 105 and replacing compound 70 with compound 68.

30997 / H

Example 122

Compound 122

Compound 122 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 106 and replacing compound 70 with compound 68.

Example 123

Compound 123

Compound 123 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 99 and replacing compound 70 with compound 69.

30997 / H

Example 124

Compound 124

Compound 124 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 99 and replacing compound 70 with compound 73.

Example 125

Compound 125

Compound 125 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 99 and replacing compound 70 with compound 71.

30997 / H

Example 126

Compound 126

Compound 126 was prepared using the same procedure as described for compound 107, replacing compound 96 with compound 99 and replacing compound 70 with compound 72.

Example 127

Compound 127

Compound 127 was prepared using the same procedure as described for compound 107, replacing compound 96 with indole-6-carboxylic acid and replacing compound 70 with compound 69.

30997 / H

Example 128

Compound 128

Compound 128 was prepared using the same procedure as described for compound 107, replacing compound 96 with indole-5-carboxylic acid and replacing compound 70 with compound 69.

Example 129

Compound 129

To a solution of Compound 107 (1.2 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) was added 2N sodium hydroxide (10 mL) dropwise at 0 ° C. The solution was allowed to warm to room temperature and stirred for 2.5 hours at room temperature. The solution is cooled to 0 ° C and 1N hydrochloric acid is added until pH 7 is reached.

30997 / H was removed in vacuo and the residue diluted with 25 mL of water. 1N hydrochloric acid is added until pH 2 and the mixture is extracted three times with 75 ml of ethyl acetate. The combined organic extracts were dried (MgSO 4), filtered, evaporated and dried in vacuo.

Dissolve 1.1 mmol of the acid in 15 mL of tetrahydrofuran and cool to -20 ° C. N-methylmorpholine (1.45 mmol) is added in one portion followed by isobutyl chloroformate (1.45 mmol) dropwise via syringe. The reaction mixture was allowed to stir at -20 ° C for 20 minutes. The reaction mixture was filtered at 0 ° C into a solution of 11 mmol of sodium borohydride in 20 mL of water. Stirring at 0 ° C was continued for 1.5 hours. The reaction mixture was diluted with 300 mL of ethyl acetate and washed three times with 150 mL of water and brine. The organic phase is dried over magnesium sulphate, filtered and evaporated. The resulting alcohol was purified by flash chromatography (hexanes: ethyl acetate 2: 3).

Example 130

Compound 130

Compound 130 was prepared as follows for compound 129, substituting compound 108 for compound 107.

30997 / H

Example 131

Compound 131

F

Compound 131 was prepared as follows for compound 129, substituting compound 109 for compound 107.

Example 132

Compound 132

Compound 132 was prepared as follows for compound 129, substituting compound 110 for compound 107.

Example 133

Compound 133

30997 / H

Compound 133 was prepared as follows for compound 129, substituting compound 112 for compound 107.

Example 134

Compound 134

Compound 134 was prepared as described for compound 129, substituting compound 113 for compound 107.

Example 135

Compound 135

30997 / H

Compound 135 was prepared as follows for compound 129, substituting compound 114 for compound 107.

Example 136

Compound 136

Compound 136 was prepared as follows for the compound. 129, replacing compound 107 with compound 115.

Example 137

Compound 137

30997 / H

Compound 137 was prepared as follows for compound 129, substituting compound 116 for compound 107.

Example 138

Compound 138

Compound 138 was prepared as follows for compound 129, substituting compound 117 for compound 107.

Example 139

Compound 139

30997 / H

Compound 139 was prepared as follows for compound 129, substituting compound 118 for compound 107.

Example 140

Compound 140

Compound 140 was prepared as follows for compound 129, substituting compound 119 for compound 107.

Example 141

Compound 141

30997 / H

Compound 141 was prepared as follows for compound 129, substituting compound 120 for compound 107.

Example 142

Compound 142

Compound 142 was prepared as follows for compound 129, substituting compound 121 for compound 107.

Example 143

Compound 143

30997 / H

Compound 143 was prepared as follows for compound 129, substituting compound 122 for compound 107.

Example 144

Compound 144

CN

Compound 144 was prepared as follows for compound 129, substituting compound 123 for compound 107.

Example 145

Compound 145

30997 / H

100

Compound 145 was prepared as follows for compound 129, substituting compound 124 for compound 107.

Example 146

Compound 146

Compound 146 was prepared as follows for compound 129, substituting compound 125 for compound 107.

30997 / H

101

Example 147

Compound 147

Compound 147 was prepared as follows for compound 129, substituting compound 126 for compound 107.

Example 148

Compound 148

To a solution of 0.5 mmol of compound 129 in 8 mL of dichloromethane was added 0.6 mmol of pyridine at 0 ° C in one portion. 0.6 mmol is added in one portion

30997 / H

102 followed by dimethylaminopyridine in a similar manner. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was partitioned between 10 mL of 0.1 N hydrochloric acid and 30 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo.

Example 149

Compound 149

Compound 149 was prepared as follows for compound 148, substituting compound 130 for compound 129.

Example 150

Compound 150

30997 / H

103

Compound 150 was prepared as follows for compound 148, replacing compound 129 with compound 131.

Example 151

Compound 151

Compound 151 was prepared as follows for compound 148, substituting compound 132 for compound 129.

Example 152

Compound 152

30997 / H

104

Compound 152 was prepared as follows for compound 148, substituting compound 133 for compound 129.

Example 153

Compound 153

Compound 153 was prepared as follows for compound 148, substituting compound 134 for compound 129.

Example 154

Compound 154

30997 / H

105

To a solution of Compound 135 (1.1 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL) at 0 ° C at once. The resulting solution was stirred at 0 ° C for 3 hours. The solvents were removed in vacuo and the residue was partitioned between 10% aqueous sodium bicarbonate and ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated in vacuo. The free amine (1.1 mmol) was dissolved in glacial acetic acid (10 ml) and paraformaldehyde (11 mmol) was added in one portion at room temperature. Stirring at room temperature is continued overnight.

The reaction mixture is taken up in 50 ml of ice-cold 2N sodium hydroxide and extracted three times with 100 ml of ethyl acetate. The combined organic extracts were backwashed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo. The desired product was purified by reverse phase HPLC using a gradient of 20% to 100% acetonitrile in water buffered with 0.1% trifluoroacetic acid.

Example 155

Compound 155

To a solution of Compound 154 (0.5 mmol) in cold acetone (10 mL) was added a large excess (2 mL) of methyl iodide at room temperature at once. The resulting solution was allowed to stir overnight at room temperature. The solvents are removed in vacuo to give the desired tetramethylammonium salt.

30997 / H

106

Example 156

Compound 156

To a solution of 0.8 mmol of compound 111 in 2 mL of dimethylformamide and 8 mL of tetrahydrofuran at 0 ° C was added 1 mmol of sodium hydride in one portion. The solution was stirred at 0 ° C for 1 hour and a large excess of methyl iodide was added in one portion. The solution was allowed to reach room temperature and stirred overnight. The reaction mixture is poured into 100 ml of ice-water and extracted three times with 75 ml of ethyl acetate. The combined organic extracts were backwashed with water, dried over magnesium sulfate, filtered, evaporated in vacuo and purified by flash chromatography (hexanes: ethyl acetate 1: 2).

Example 157

Compound 157

30997 / H

107

Compound 157 was prepared in the following manner as described for compound 154, substituting compound 123 for compound 135.

Example 158

Compound 158

Compound 158 was prepared as follows for compound 155 with the starting compound 157.

Example 159a

Compound 159

30997 / H

108

To a solution of 1 mmol of 129 in 50 mL of cold methanol was added crushed 3 x 10 &^lt; ^{10 &gt;} m molecular sieves (approximately 1 g). The mixture was stirred for 10 minutes at 0 ° C. Hydrochloric acid was bubbled through the reaction mixture for 10 minutes at 0 ° C. The reaction mixture was allowed to reach room temperature and stirred overnight. Nitrogen gas was bubbled through the reaction mixture for 5 minutes and the methanol was removed in vacuo. The residue is dried under vacuum to remove any traces of hydrochloric acid and then mixed with 75 ml of cold methanol again. The mixture was then cooled to 0 ° C and ammonia gas was bubbled through the reaction mixture for 10 minutes. The reaction mixture was allowed to reach room temperature and then heated at 60 ° C for 3 hours. After cooling to room temperature, nitrogen gas was bubbled through the reaction mixture for 5 minutes and then the mixture was filtered through celite, evaporated in vacuo and purified by reverse phase HPLC using a gradient of 20% to 80% acetonitrile in water buffered with 0.1% trifluoroacetic acid. The acetonitrile is removed in vacuo and the aqueous phase is lyophilized to give the desired product as the trifluoroacetate salt.

Example 159b

Compound 159

¹ H NMR (300 MHz, d ₆ -DMSO): d 9.21 (s, 2H), 9.01 (s, 2H), 8.22 (d, 1H, J = 9.6 Hz), 7, 85 (d, 2H, J = 7.2Hz), 7.70 (d, 2H, J = 7.2Hz), 7.62-7.38 (m, 4H), 7.25

30997 / H

109

7.05 (m, 7H), 6.93 (d, 1H, J = 8.4 Hz), 4.90-4.65 (m, 1H), 4.24 (s, 4H), 18-4.05 (m, 2H), 2.78-2.63 (m, 2H), 2.65-2.45 (m, 2H), 2.08-1.75 (m, 3H).

MS, LRFAB, calc. 591, found 592 (M + H) +.

To a solution of 1 mmol of 129 in 20 mL of pyridine and 4 mL of triethylamine was bubbled hydrogen sulfide at room temperature for 10 minutes. The reaction mixture was allowed to stir overnight at room temperature. Nitrogen gas was bubbled through the reaction mixture for 5 minutes and the solvents were removed in vacuo. The residue is dried under vacuum, then dissolved in 15 ml of cold acetone. To this solution was added 5 ml of methyl iodide and the solution was heated at 50 ° C for 1 hour, then evaporated in vacuo. The residue was dissolved in 20 ml of methanol, and 2 mmol of ammonium acetate were added at once at room temperature. The reaction mixture was heated at 65 ° C for 2 hours. After cooling, the methanol was evaporated in vacuo and the residue was purified by reverse phase HPLC using a gradient of 20% to 80% acetonitrile in water buffered with 0.1% trifluoroacetic acid. The acetonitrile is removed in vacuo and the aqueous phase is lyophilized to give the desired product, such as the trifluoroacetate salt.

The following compounds are prepared from the appropriate starting materials by procedures substantially similar to those described above.

S Example 161

Compound 161

30997 / H

110.1 1 H NMR (300 MHz, d ₆ -DMSO): d 9.23 (s, 2H), 8.27 (d, 1H, J = 9.6 Hz), 7.93 (d, 2H, J = 7.2 Hz), 7.72 (d, 2H, J = 7.2 Hz), 7.65-7.55 (m, 2H), 7.54-7.42 (m, 2H), 28-7.08 (m, 7H), 6.94 (d, 1H, J = 8.4 Hz), 4.25 (s, 1H), 4.24-4.11 (m, 1H), 4.053.83 (m, 2H), 2.86 (dd, 1H, J = 6.0, 15.6 Hz), 2.70-2.55 (m, 2H), 2.53-2.43 ( m, 1H), 2.35-2.20 (m, 1H), 1.98-1.90 (m, 2H), 1.87 (s, 3H).

MS, LRFAB, calc. 591, found 592 (M + H) ⁺ .

Example 162

Compound 162

¹ H NMR (300 MHz, d ₆ -DMSO): d 9.21 (s, 2H), 9.01 (s, 2H), 8.22 (d, 1H, J = 9.6 Hz), 7 85 (d, 2H, J = 7.2Hz), 7.70 (d, 2H, J = 7.2Hz), 7.62-7.38 (m, 4H), 7.257.05 (m, 7H), 6.93 (d, 1H, J = 8.4 Hz), 4.90-4.65 (m, 1H), 4.24 (s, 4H), 4.18-4.05 ( m, 2H), 2.78-2.63 (m, 2H), 2.65-2.45 (m, 2H), 2.08-1.75 (m, 3H).

MS, LCRFAB, calc. 591, found 592 (M + H) ⁺ .

30997 / H

111

Example 163

Compound 163

¹ H NMR (300 MHz, d ₆ -DMSO): d 9.23 (s, 2H), 9.09 (s, 2H), 8.83 (d, 1H, J = 9.6 Hz), 7 97 (d, 2H, J = 7.2Hz), 7.83 (d, 2H, J = 7.2Hz), 7.65-7.35 (m, 7H), 7.287.05 (m, 6H), 4.26-4.10 (m, 1H), 4.05-3.83 (m, 2H), 2.87 (dd, 1H, J = 6.0 Hz,

15.6 Hz), 2.70-2.55 (m, 2H), 2.32-2.18 (m, 1H), 2.03-1.90 (m, 2H), 1.87 (s , 3H). MS, ion spray, calc. 551, found 552 (M + H) ⁺ .

30997 / H

112

Example 164

Compound 164

¹ H NMR (300 MHz, d ₆ -DMSO): d 9.22 (s, 2H), 9.02 (s, 2H), 8.32 (d, 1H, J = 9.6 Hz), 7, 96 (d, 2H, J = 7.2Hz), 7.81-7.65 (m, 4H), 7.65-7.40 (m, 4H), 7.38-7.05 (m, 7H), 4.25-4.10 (m, 1H), 4.05-3.85 (m, 2H), 2.87 (dd, 1H, J = 6.0, 15.6 Hz), 2 , 70-

2.55 (m, 2H); 2.54-2.43 (m, 1H); 2.35-2.20 (m, 1H); 1.98-1.90 (m, 2H); 89 (s, 3 H).

MS, ion spray, calc. 551, found 552 (M + H) ⁺ .

Example 165

Compound 165

30997 / H

113 ¹ H NMR (300 MHz, d ₆ -DMSO): d 9.25 (s, 2H), 9.18 (s, 2H), 8.35 (d, 1H, J = 9.6 Hz), 7 80 (d, 2H, J = 7.2Hz), 7.73 (d, 2H, J = 7.2Hz), 7.68 (d, 2H, J = 6.0Hz), 7.62 (broad s, 2H), 7.55-7.31 (m, 5H), 7.25-7.03 (m, 5H), 4.65-4.45 (m, 1H), 3.53 ( s, 3H), 3.20-2.82 (m, 5H).

MS, LRFAB, Calcd 505, Found 506 (M + H) ⁺ .

Example 166

Compound 166

¹ H NMR (300 MHz, d ₆ -DMSO): d 9.23 (s, 2H), 8.99 (s, 2H), 8.26 (d, 1H,> 9.6 Hz), 7.93 (d, 2H, > 7.2 Hz), 7.72 (d, 2H, J = 7.2 Hz), 7.65-7.56 (m, 2H), 7.54-

7.42 (m, 2H), 7.32 (d, 1H, J = 2.4 Hz), 7.28-7.08 (m, 6H), 7.02 (d, 1H,> 8.4) Hz), 6.07 (s, 2H), 4.25-4.12 (m, 1H), 4.06-3.85 (m, 2H), 2.85 (dd, 1H,> 6, 0. 15.6 Hz), 2.68-2.55 (m, 2H), 2.53-2.43 (m, 1H), 2.32-2.20 (m, 1H), 2.01 -1.90 (m, 2H), 1.87 (s, 3H).

MS, LRFAB, Calcd 557, Found 558 (M + H) ⁺ .

30997 / H

114

Example 167

Compound 167

NMR: 9.5 (s, 1H), 9.4 (s, 1H), 8.4 (d, 1H, J = 9.0 Hz), 8.1 (d, 2H, J = 8.0) Hz), 7.9 (d, 2H, J = 8.0 Hz), 7.5-7.8 (m, 5H), 7.1-7.4 (m, 7H), 5.0 (m 1H, 4.0-4.1 (m, 1H), 4.0 (s, 3H), 3.0 (s, 3H), 3.6 (m, 1H), 2.9-3 1 (m, 4H), 2.1-2.3 (m, 2H), 2.0 (s, 3H).

MS calc. 594.3, found 594.

Example 168

Compound 168

30997 / H

115

NMR: 9.4 (s, 1H), 8.4 (d, 1H, J = 9.0 Hz), 8.1 (d, 2H, J = 7.0 Hz), 7.9 (d, 2H, J = 7.0 Hz), 7.5-7.8 (m, 5H), 7.1-7.4 (m, 7H), 5.0 (m, 1H), 4.0-4 1 (m, 1H), 4.0 (s, 3H), 3.0 (s, 3H), 3.6 (m, 1H), 2.9-3.1 (m, 4H), 2, 1-2.3 (m, 2 H).

MS calcd 552.1, found 552.

Example 169

Compound 169

¹ H NMR (300 MHz, d ₆ -DMSO): d 9.22 (s, 2H), 9.11 (s, 2H), 7.92 (d, 2H, J = 7.2 Hz), 7, 80-7.65 (m, 4H), 7.62-7.40 (m, 4H), 7.37-7.01 (m, 7H), 4.85-4.65 (m, 1H), 4.22-4.02 (m, 1H), 3.55-3.36 (m, 2H), 2.82-2.62 (m, 2H), 2.60-2.45 (m, 1) H, 2.05-1.73 (m, 3H).

MS, LRFAB, Calcd 509, Found 510 (M + H) ⁺ .

30997 / H

116

Example 170

Compound 170

NMR: 8.5 (d, 1H, J = 9.0 Hz), 7.8 (d, 2H, J = 9.0 Hz), 7.7 (d, 2H, J = 9.0 Hz) , 7,1-

7.6 (m, 11H), 4.5 (m, 1H), 4.4 (s, 2H), 4.0 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.7 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.0 (d, 2H, J = 9.0 Hz), 2.9 (d, 2H, J = 9.0 Hz), 2, O (d, 1H, J = 7.0Hz).

MS (M + H) ⁺ calc. 549.2, found 549.

Example 171

Compound 171

NMR: 8.5 (d, 1H, J = 9.0 Hz), 7.75-7.9 (m, 6H), 7.4-7.7 (m, 6H), 7.0-7, 2 (m, 5 H).

4.4 (m, 1H), 4.2 (s, 2H), 4.0 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.7 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.0 (d, 2H, J = 9.0 Hz), 2.9 (d, 1H, J = 9.0 Hz), 2.0 (m, 1H).

30997 / H

117

MS (M + H) ⁺ calcd 507.3, found 507.

Example 172

Compound 172

NMR: 8.5 (d, 1H, J = 9.0Hz), 7.8 (d, 2H, J = 10Hz), 7.7 (d, 2H, J = 10Hz), 7.6 ( d, 1H, J = 10 Hz), 7.5 (m, 3H), 7.0-7.3 (m, 8H), 6.8 (d, 1H, J = 9.0 Hz), 4, Δ (m, 3H),

4.1 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.9 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.1 (d, 2H, J = 9, 0 Hz), 2.9 (d, 2H, J = 9.0 Hz), 2.0 (m, 1H).

MS (M + H) ⁺ calcd 494.2, found 494.

30997 / H

118

Example 173

Compound 173

NHAc

NMR: 8.5 (d, 1H, J = 9.0 Hz), 7.9 (d, 2H, J = 10 Hz), 7.8 (d, 2H,> 10 Hz), 7.7 (d 2H, J = 10Hz), 7.6 (d, 2H, J = 10Hz), 7.4 (s, 1H), 7.0-7.2 (m, 3H), 4.5 (m , 3H),

4.1 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.9 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.1 (d, 2H, J = 9, 0 Hz), 2.9 (d, 2H, J = 9.0 Hz), 2.1 (d, 3H, J = 10 Hz).

MS (M + H) ⁺ calc. 549.3, found 549.

Example 174

Compound 174

30997 / H

119

NMR: 8.5 (d, 1H, J = 9.0 Hz), 7.8 (d, 2H, J = 8.0 Hz), 7.6-7.8 (m, 4H), 7.4 -7.6 (m, 4H), 7.0-7.3 (m, 4H), 6.8 (d, 2H, J = 9.0 Hz), 4.3 (m, 1H), 4.0 ( dd, 1H, J = 6.0 Hz, 10 Hz), 3.7 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.0 (d, 2H, J = 4.0 Hz) 1.2 (d, 1H, J = 9.0 Hz), 2.0 (d, 1H).

MS (M + H) ⁺ , calcd 507.3, found 507.

Example 175

Compound 175

MS calcd 494.2, found 494.

Example 176

Compound 176

30997 / H

120

NMR (300 MHz, d ₆ -DMSO): d 9.23 (s, 2H), 9.04 (s, 2H), 8.57 (d, 1H, J = 9.6 Hz),

8.42 (s, 1H), 8.32 (d, 2H, J = 7.2 Hz), 8.13 (dd, 1H, J = 1.2, 7.2 Hz), 7.75- 7.40 (m, 7H), 7.25-7.13 (m, 4H), 7.12-7.05 (m, 2H), 4.48-4.35 (m, 1H), 3, 58-3.42 (m, 2H); 3.10-2.62 (m, 4H); 2.15-1.95 (m, 1H).

MS, LRFAB, Calcd. 567, Found 568 (M + H) ⁺ .

Example 177

Compound 177

NMR (300 MHz, d ₆ -DMSO): d 9.23 (s, 2H), 8.98 (s, 2H), 8.37-8.22 (m, 3H), 7.97 (d, 2H) J = 7.2 Hz), 7.86 (s, 4H), 7.65-7.40 (m, 4H), 7.25-7.15 (m, 3H), 7.13-7, 05 (m, 2H), 4.45-4.25 (m, 1H), 3.62-3.48 (m, 2H), 3.00-2.86 (m, 2H), 2.85- 2.65 (m, 2H); 2.06-1.92 (m, 1H).

MS, LRFAB, Calcd 522, Found 523 (M + H) ⁺ .

Example 178

Compound 178

30997 / H

121

NMR (300 MHz, d ₆ -DMSO): 9.23 (d, 4H, J = 6Hz), 8.28 (d, 1H, J = 10Hz), 7.77 (d, 2H, J = 10 Hz), 7.71-7.42 (m, 8H), 7.22-7.12 (m, 4H), 7.10-7.01 (m, 3H),

4.45-4.25 (m, 1 H), 3.65-3.45 (m, 2 H), 3.05-2.87 (m, 2 H), 2.85-2.65 (m, 2 H) 1.05-1.55 (m, 1H).

MS, LRFAB, Calcd 492, Found 493 (M + H) ⁺ .

Example 179

Compound 179

NMR (300 MHz, d ₆ -DMSO): 9.38-9.21 (m, 4H), 8.28 (d, 1H, J = 10Hz), 8.16 (d, 1H, J = 10Hz) 7.70-7.45 (m, 5H), 7.42 (d, 2H, J = 7Hz), 7.23 (s, 1H), 7.21-7.03

30997 / H

122 (m, 8H), 4.48-4.23 (m, 1H), 3.64-3.40 (m, 2H), 3.10-2.85 (m, 2H), 2.84- 2.62 (m, 2H); 2.03-1.87 (m, 1H).

MS, LRFAB, Calcd 507, Found 508 (M + H) ⁺ .

Example 180

Compound 180

NMR (300 MHz, d ₆ -DMSO): d 9.23 (s, 2H), 8.95 (s, 2H), 8.45 (s, 1H), 8.32 (d, 1H, J = 8) 4 Hz), 8.24 (d, 1H, J = 8.4 Hz), 8.18 (d, 1H, J = 7.2 Hz), 7.86 (broad s, 4H), 7.83 -7.73 (m, 1H), 7.63-7.43 (m, 4H), 7.25-7.16 (m, 4H), 7.14-7.05 (m, 1H), 4 45-4.30 (m, 1H); 3.63-3.48 (m, 2H); 3.02-2.88 (m, 2H); 2.87-2.65 (m, 2H) 2.08-1.93 (m, 1H).

MS, LRFAB, Calcd 522, Found 523 (M + H) ⁺ .

30997 / H

123

Example 181

Compound 181

NMR (300 MHz, d ₆ -DMSO): 9.25 (s, 2H), 9.19 (s, 2H), 8.30 (d, 1H, J = 9.6 Hz),

7.86 (s, 1H), 7.82 (d, 2H, J = 7.2Hz), 7.66 (d, 2H, J = 7.2Hz), 7.63-7.45 (m) 4H), 7.38-7.27 (m, 1H), 7.25-7.13 (m, 6H), 7.13-7.05 (m, 1H), 6.93 (d, 1H) J = 8.4 Hz), 4.43-4.28 (m, 1H), 3.65-3.45 (m, 2H), 3.05-2.86 (m, 2H), 2, 83-2.68 (m, 2H); 2.08-1.92 (m, 1H).

MS, LRFAB, Calcd 492, Found 493 (M + H) ⁺ .

Example 182

Compound 182

NHAc

30997 / H

124

NMR (300 MHz, d ₆ -DMSO): 9.22 (s, 2H), 9.07 (s, 2H), 8.38 (d, 1H, J = 10 Hz),

7.93 (s, 1H), 7.83 (d, 2H, J = 7.0 Hz), 7.65 (d, 2H, J = 7.0 Hz), 7.62-7.45 (m) 5H), 7.42-7.28 (m, 2H), 7.25-7.16 (m, 4H), 7.13-7.07 (m, 1H), 4.45-4.28 (m, 1H), 3.63-3.53 (m, 2H), 3.05-2.87 (m, 2H), 2.85-2.68 (m, 2H), 2.03 (s 3H), 2.02-1.93 (m, 1H).

MS, LRFAB calc. 534, found 535 (M + H) +.

Example 183

Compound 183

NMR (300 MHz, d ₆ -DMSO): 10.05 (s, 1H), 9.23 (s, 2H), 9.10 (s, 2H), 8.25 (d, 1H, J = 10 Hz) 7.78 (d, 2H, J = 7.0 Hz), 7.73-7.40 (m, 10H), 7.21-7.13 (m, 4H), 7.13-7, Δ (m, 1H), 7.25-7.13 (m, 6H), 4.43-4.25 (m, 1H). 3.63-3.45 (m, 2H); 3.03-2.85 (m, 2H). 2.83-2.68 (m, 2 H). 2.04 (s, 3H); 2.01-1.93 (m, 1H).

MS, LRFAB calc. 534, found 535 (M + H) +.

Example 184

Compound 184

30997 / H

125

NMR: 8.30 (d, 1H, J = 7.0 Hz), 7.8-8.0 (m, 6H), 7.4-7.7 (m, 6H), 7.1-7, 3 (m, 5 H),

4.6 (m, 3H), 4.1 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.7 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.0 (d, 2H, J = 9.0 Hz), 2.9 (d, 2H, J = 9.0 Hz), 2.9 (s, 6H), 2.0 (m, 1H).

MS (M + H) + calcd 535.3, found 535.

Example 185

Compound 185

NMR: 8.5 (d, 1H, J = 7.0 Hz), 7.8-8.0 (m, 6H), 7.4-7.7 (m, 6H), 7.1-7, 3 (m, 5 H),

4.6 (m, 3H), 4.0 (dd, 1H, J = 6.0 Hz, 10 Hz), 3.6 (dd, 1H, J = 6.0 Hz, 10.0 Hz), 3 2 (s, 9H), 3.0 (d, 2H, J = 9.0 Hz), 2.9 (d, 2H, J = 9.0 Hz), 2.0 (m, 1H).

MS (M + H) ⁺ calc. 549.3, found 549.

30997 / H

126

Example 186

Compound 186

¹ H NMR (300 MHz, d ₆ -DMSO): d 9.30-9.11 (m, 3H), 8.31 (broad s, 2H), 8.15 (d, 1H, J = 8.4 Hz), 7.93 (d, 2H, J = 7.2 Hz), 7.86-7.68 (m, 2H), 7.64-7.48 (m, 6H),

4.30-4.15 (m, 1H), 4.14-4.04 (m, 2H), 2.75 (d, 2H, J = 6.0 Hz), 1.95-1.82 ( m, 1H), 1.80-1.68 (m, 2H), 1.65-1.46 (m, 5H), 1.42-1.32 (m, 1H), 1.31-1, 15 (m, 1H), 1.13-0.93 (m, 2H), 0.92-0.65 (m, 4H).

MS, LRFAB, Calcd 516, found 513 (M + H) ⁺ .

Example 187

Compound 187

30997 / H

127

NMR: 9.0 (s, 1H), 8.5 (d, 1H, J = 9.0 Hz), 7.9 (d, 2H, J = 9.0 Hz), 7.6-7.8 (m, 4H)

7.3-7.5 (m, 6H), 7.2-7.1 (m, 6H), 3.5 (s, 3H). 3.1 (s, 3H), 3.0 (d, 2H, J = 8.0Hz),

2.9 (d, 2H, J = 8.0Hz).

MS calcd 520.1, found 520.

Example 188

Compound 188

NMR: 9.4 (d, 1H, J = 12.0 Hz), 8.6 (d, 1H, J = 10.0 Hz), 8.1 (d, 2H, J = 10 Hz), 7 9-

8.1 (m, 4H), 7.6-7.8 (m, 6H), 4.7 (m, 1H), 4.4 (d, 2H, J = 9.0 Hz), 3.7 (s, 3H), 3.1-

3.4 (m, 4H), 1.6 (d, 3H, J = 9.0 Hz).

MS (M + H + calc 459.2, found 459).

Example 189 sec ·

Compound 189

30997 / H

128

NMR: 9.4 (d, 1H, J = 12.0 Hz), 8.0 (d, 1H, J = 10.0 Hz), 8.1 (d, 2H, J = 10 Hz), 7 , 7-

7.9 (m, 4H), 7.4-7.6 (m, 6H), 4.5 (m, 1H), 4.2 (d, 2H, J = 9.0 Hz), 3.6 (s, 3H), 3.0-

3.2 (m, 3H), 1.6 (d, 3H, J = 9.0 Hz).

MS (M + H) ⁺ calcd 475.1, found 475.

Example 190

Compound 190

NMR: 8.4 (d, 1H, J = 9.0 Hz), 7.9 (d, 2H, J = 10 Hz), 7.7-7.90 (m, 4H), 7.4- 7.6 (m, 6H), 4.7 (m, H), 4.5 (s, 2H), 3.6 (s, 3H), 3.1-3.2 (m, 3H), 2 9 (s, 6H), 1.3 (d, 3H, J = 9.0 Hz).

MS (M + H) ⁺ calcd 459.2, found 459.

t »

30997 / H

129

Example 191

Compound 191

NMR: 9.3 (d, 1H, J = 9.0 Hz), 9.1 (d, 1H, J = 9.0 Hz), 8.4 (d, 1H, J = 10 Hz), 7, 7-8.0 (m, 4H), 7.3-7.6 (m, 5H), 4.6 (s, 2H), 4.4 (m, 1H), 3.5 (s, 3H) 3.1 (s, 9H), 2.9-

3.1 (m, 3H), 1.6 (d, 3H, J = 9.0 Hz).

MS (M + H) ⁺ calcd 501.1, found 501.

Example 192

Compound 192

30997 / H

130

MS, APCI calcd 392, found 393 (M + H) ⁺ .

Example 193

Compound 193

MS, APCI calcd 392, found 393 (M + H) ⁺ .

Example 194

Compound 194

30997 / H

131

NMR: 9.4 (d, 1H, J = 12.0 Hz), 8.6 (d, 1H, J = 10.0 Hz), 8.0 (d, 2H, J = 9.0 Hz) 7.7 (d, 2H, J = 9.0 Hz), 7.3-7.6 (m, 6H), 7.0-7.2 (m, 2H), 4.2 (m, 3H), 4.0 (dd, 1H, J = 6.0 Hz, 10.0 Hz), 3.6 (dd, 1H, J = 6.0 Hz, 10.0 Hz), 3.0 (d H, J = 8.0 Hz), 2.0 (m, 1H), 1.6 (m, H), 1.1-1.3 (m, 8H).

MS (M + H) ⁺ calcd 473.1, found 473.

Example 195

Compound 195

Example 196

Compound 196

30997 / H

132

BOCNH O

Example 197

Compound 197

To a stirred solution of 8.9 g (50 mmol) of acetic acid methyl ester of (R) -3-aminobutyrate and 21 ml (150 mmol) of triethylamine in cold dichloromethane at room temperature under a nitrogen atmosphere is added dropwise 21.8 g (100 mmol). tert-dibutyl carbonate. About 50 mg of dimethylaminopyridine is then added and the mixture is allowed to stir at room temperature overnight. At this point, the mixture is washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product is chromatographed (eluent is a 20% to 40% ethyl acetate in hexanes solution) to give compound 197.

¹ H NMR (CDCl 3, d): 4.92 (bs, 1H), 3.96 (bm, 1H), 3.65 (s, 3H), 2.45-2.37 (m, 2H), 1 39 (s, 9H), 1.16 (d, J = 7.9Hz, 3H).

Example 198

Compound i 98

BOCNH O

30997 / H

133

To a stirred solution of 2.00 g (9.21 mmol) of compound 197 in 50 mL of cold tetrahydrofuran at -78 ° C under nitrogen was added dropwise 25.8 mL of a 1M solution of lithium hexamethyldisilazane in tetrahydrofuran. The mixture is then heated to -20 C C to -25 C for 30 minutes and then cooled back to -78 C. C. A solution of 5.41 g (23 mmol) of 3-cyanobenzyl bromide in cold tetrahydrofuran is then added dropwise and the resulting solution is allowed to warm to room temperature. After 1 hour at room temperature, the mixture was quenched with saturated sodium bicarbonate solution and most of the tetrahydrofuran was evaporated in vacuo. The residue was taken up in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (eluent was 25% ethyl acetate in hexanes). The semi-solid residue was then triturated with 20% ethyl acetate in hexanes and the white solid was filtered off. The filtrate was then evaporated in vacuo to give compound 198.

¹ H NMR (CDCl ₃ , d): 7.25-7.50 (m, 4H), 5.21 (bd, 1H), 3.88 (m, 1H), 3.60 (s, 3H), 3.07-2.73 (m, 3H), 1.48 (s, 9H), 1.14 (d, J = 7.9 Hz, 3H).

Example 199

Compound 199

To a stirred solution of Compound 198 (4.20 g, 12.7 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL) at room temperature under nitrogen. The mixture was allowed to stir overnight at room temperature and then evaporated in vacuo to give 4.20 g of compound 199 as the trifluoroacetic acid salt.

30997 / H

134 ¹ H NMR (DMSO-d 6, d): 8.07 (bs, 1H), 7.73-7.43 (m, 4H), 3.50 (s, 3H), 3.51 (m, 1H) 1.05, 3.05-2.82 (m, 3H), 1.23 (d, J = 7.9 Hz, 3H).

Alternatively, compound 4 can be prepared as shown below.

Example 200

Compound 200

PhCH ₂ OCONH O

To a stirred solution of 6.98 g (39.4 mmol) of D-3-aminobutyric acid methyl ester salt in 40 mL of dichloromethane was added 40 mL of saturated sodium bicarbonate solution. 9.0 ml (63 mmol) of benzyl chloroformate are then added dropwise and the mixture is allowed to stir vigorously at room temperature. After 3 hours, the organic layer was separated and washed with water, the organic layer was dried over sodium sulfate, filtered and evaporated. The crude product is chromatographed (eluent is 10% ethyl acetate in chloroform) to give compound 200.

¹ H NMR (CDCl 3, d): 7.40-7.22 (m, 5H), 5.25 (m, 1H), 5.08 (s, 2H), 4.11 (m, 1H), 3 65 (s, 3H), 2.53 (d, J = 7.0 Hz, 2H), 1.23 (d, J = 7.9 Hz, 3H).

Example 201

Compound 201

30997 / H

135

To a stirred solution of 3.45 g (13.71 mmol) of compound 200 in 20 mL of tetrahydrofuran at -78 ° C under a nitrogen atmosphere was added dropwise 41.2 mL of 1.0 M LHMDS solution. The mixture was then warmed to -20 ° C for 30 minutes and then recooled to -78 ° C. A solution of 4.51 g (23.0 mmol) of 3-cyanobenzyl bromide in cold tetrahydrofuran is then added dropwise and the resulting solution is allowed to warm to room temperature. After 1 hour at room temperature, the mixture was quenched with saturated sodium bicarbonate solution and most of the tetrahydrofuran was evaporated in vacuo. The residue was taken up in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (eluent 30% ethyl acetate in hexanes). The semi-solid residue was then triturated with 20% ethyl acetate in hexanes and the white solid was filtered off. The filtrate was then evaporated in vacuo to give compound 201.

¹ H NMR (CDCl 3, d): 7.20-7.65 (m, 9H), 5.57 (bd, 1H), 5.12 (s, 2H), 3.97 (m, 1H), 3 60 (s, 3H), 3.07-2.75 (m, 3H), 1.16 (d, J = 7.9 Hz, 3H).

Example 202

Compound 202

To a stirred solution of 2.6 g (7.1 mmol) of 201 in 25 mL of ethanol was added 520 mg of 10% palladium on carbon. The mixture was stirred at room temperature for 3 hours under hydrogen pressure of 10 ⁵ Pa. The mixture was then filtered through a pad of celite to remove the catalyst. The filtrate was then evaporated in vacuo to yield

1.45 g of compound 201.

30997 / H

136

Example 203

Compound 203

384 mg (1.8 mmol) of 3'-pyridyl-4-phenylcarbonyl chloride (compound 228, prepared according to Example 228) is added in one portion at room temperature under a nitrogen atmosphere to a solution of 373 mg (1.6 mmol) of the trifluoroacetic acid salt 199 and 0.67 ml (4.8 mmol) of triethylamine in 5.0 ml of pure ethanol. The mixture was allowed to stir overnight at room temperature. The solvent was then evaporated in vacuo and the crude product was purified by silica gel chromatography (eluent 70% ethyl acetate in hexanes) to give compound 203.

¹ H NMR (CDCl ₃ , d): 8.88 (m, 1H), 8.63 (m, 1H), 7.85-8.00 (m, 7.70, 2H), 7.577.33 (m (6H), 4.51 (m, 1H). 3.65 (s, 3H), 3.10-2.82 (m, 3H), 1.28 (d, J = 7.9 Hz, 3H).

Example 204

Compound 204

30997 / H

137

Acylation of compound 199 according to the procedure of Example 203 substituting 228 for 4'-pyridyl-4-phenylcarbonyl chloride (Compound 231 prepared according to Example 231) gave Compound 204 after workup and chromatography. ¹ H NMR (CDCl ₃ , d): 8.70 (m) 2H, 8.02-7.65 (m, 4H), 7.57-7.32 (m, 7H), 4.50 (m, 1H), 3.68 (s, 3H), 3, 10-2.83 (m, 3H); 1.30 (d, J = 7.9 Hz, 3H).

Example 205

Compound 205

Acylation of compound 199 according to the procedure of Example 203, performed in dichloromethane rather than pure ethanol and replaced with 3'-pyridyl-4-phenylcarbonyl chloride with 4-biphenylcarbonyl chloride, yields compound 205 after work-up and chromatography.

¹ H NMR (CDCl ₃ , d): 7.93 (m, 2H), 7.73-7.30 (m, 12H), 4.50 (m, 1H), 3.66 (s, 3H), 3.10-2.83 (m, 3H), 1.26 (d, J = 7.9 Hz, 3H).

Example 206 *

II

Compound 206

30997 / H

138

Acylation of compound 199 according to the procedure of Example 203 substituting 3'-pyridyl-4-phenylcarbonyl chloride for 2-biphenylcarbonyl chloride affords compound 206 after work-up and chromatography.

¹ H NMR (CDCl 3, d): 7.55-7.27 (m, 5H), 7.07 (m, 2H), 6.85-6.66 (m, 5H), 4.44 (m, 1H), 3.65 (s, 3H), 3.05-2.80 (m, 3H), 1.23 (d, J = 7.9 Hz, 3H).

Example 207

Compound 207

M-Perchlorobenzoic acid (381 mg, 2.21 mmol) was added to a solution of Compound 204 (608 mg, 1.47 mmol) in dichloromethane (10 ml) at room temperature under a nitrogen atmosphere. The resulting mixture was allowed to stir overnight at room temperature. At this point, the mixture is diluted with dichloromethane and washed with 5% sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered and evaporated to give Compound 207.

MS: (M + H) ⁺ (calc) = 430, found (FAB) = 430.

»X

30997 / H

139

Example 208

Compound 208 o

IN*.

124 mg (0.72 mmol) of m-perchlorobenzoic acid was added to a solution of 150 mg (0.36 mmol) of compound 203 in 10 ml of dichloromethane at room temperature under a nitrogen atmosphere. The resulting mixture was allowed to stir overnight at room temperature. At this point, the mixture is diluted with dichloromethane and washed with 5% sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered and evaporated to give compound 208.

¹ H NMR (CDCl ₃ , d): 8.57 (m, 1H), 8.30 (m, 1H), 7.95 (m, 2H), 7.73-7.35 (m, 9H), 4.50 (m, 1H), 3.68 (s, 3H), 3.07-2.85 (m, 3H), 1.20 (d, J = 7.9 Hz, 3H).

Example 209

Compound 209

Hydrochloric acid gas was bubbled into a solution of 480 mg of compound 207 in 5 mL of cold methanol containing 3 x 10 ^-1 m molecular sieves (about 50 mg of pellets) at room temperature for 2 minutes. mixture

30997 / H

140 was allowed to stir overnight at room temperature and then evaporated in vacuo. 5 ml of a 7N solution of ammonia in methanol was added to the mixture under reflux for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by reverse phase HPLC (CH ₃ CN / water, 0.1% trifluoroacetic acid, gradient 10% to 100% CH ₃ CN) and the fractions were lyophilized to afford compound 209.

¹ H NMR (methanol-d ₄ , d): 8.42 (m, 2H), 8.00-7.85 (m, 6H), 7.68-7.47 (m, 4H), 4.47 (m, 1H), 3.60 (s, 3H), 3.18-3.00 (m, 3H), 1.33 (d, J = 7.9 Hz, 3H).

MS: (M + H) + (calc) = 447, found (FAB) = 447.

Example 210

Compound 210

Treatment of compound 203 in a similar manner to Example 209 affords compound 210 after purification by reverse-phase HPLC.

¹ H NMR (DMSO-d 6, d): 9.36 (m, 3H), 8.50-8.27 (m, 2H), 8.00-7.80 (m, 3H), 7.80- 7.40 (m, 4H), 4.40 (m, 1H), 3.49 (s, 3H), 3.13-2.81 (m, 3H), 1.25 (d, J = 7) (9 Hz, 3H).

MS: (M + H) ⁺ (calc) = 431, found (FAB) = 431.

30997 / H

141

Example 211

Compound 211

Treatment of compound 204 in a similar manner to that described in Example 209 affords compound 211 after purification by reverse-phase HPLC.

Example 216

Compound 216

Treatment of Compound 205 in a similar manner to Example 209 above yields Compound 216 after purification by reverse-phase HPLC.

¹ H NMR (DMSO-d 6, d): 9.30 (s, 1H), 9.00 (s, 1H), 8.40 (m, 1H), 8.05-7.40 (m, 12H) 4.46 (m, 1H), 3.56 (s, 3H), 3.20-2.97 (m, 3H), 1.28 (d, J = 7.9 Hz, 3H).

MS: (M + H) ⁺ (calc) = 430, found (FAB) = 430.

30997 / H

142

Example 217

Compound 217

Treatment of compound 208 in a similar manner to Example 209 above affords compound 217 after purification by reverse-phase HPLC.

¹ H NMR (methanol-d ₄ , d): 8.67 (m, 1H), 8.50-8.35 (m, 2H), 8.00-7.78 (m, 5H), 7.72 -7.48 (m, 5H), 4.47 (m, 1H), 3.60 (s, 3H), 3.16-3.05 (m, 3H), 1.32 (d, J = 7.9 Hz, 3H).

MS: (M + H) ⁺ (calc) = 447, found (FAB) = 447.

Example 218

Compound 218 W. nh F

Hydrogen sulfide gas was bubbled into a solution of 498 mg (1.21 mmol) of compound 203 in 5.0 mL pyridine and 1.0 mL triethylamine for 2 min. The resulting mixture was allowed to stir overnight at room temperature and then evaporated to dryness under a stream of nitrogen. The residue is taken up in 5 ml of dichloromethane and 5 ml is added

30997 / H

143 methyl iodide. The mixture was refluxed for 3 hours, allowed to cool to room temperature and evaporated in vacuo. The residue is taken up in 5 ml of cold methanol and 300 mg of ammonium acetate are added. The resulting mixture was refluxed for 3 hours and then evaporated in vacuo. The crude product was purified by reverse phase HPLC (CH 3 CN / water, 0.1% trifluoroacetic acid, gradient 10% to 100% CH ₃ CN) and the fractions containing the product were lyophilized to give compound 218.

¹ H NMR (methanol-d ₄ , d): 9.35 (s, 1H), 8.92 (m, 2H), 8.50 (d, 1H), 8.17 (m, 1H), 8, 08-7.92 (m, 4H), 7.66-7.50 (m, 4H), 4.50 (s, 3H), 4.50 (m, 1H), 3.58 (s, 3H) 3.15-3.02 (m, 3H), 1.34 (d, J = 7.9 Hz, 3H).

MS: M + (calculated) = 445, found (FAB) = 445.

Example 219

Compound 219

Treatment of compound 204 in a manner similar to Example 218 above for compound 203 affords compound 219 after purification by reverse-phase HPLC.

¹ H NMR (DMSO-d 6, d): 9.05 (m, 1H), 8.55 (m, 3H), 8.20-7.97 (m, 5H), 7.657.47 (m, 4H) ), 4.33 (s, 3H), 4.10 (m, 1H), 3.13 (s, 3H), 3.13-2.90 (m, 3H), 1.27 (d, J) = 7.9 Hz, 3H).

MS: M ⁺ (Calc) = 445, Found (FAB) = 445.

30997 / H

144

Example 220

Compound 220

Treatment of compound 206 in a manner similar to Example 218 above for compound 203 affords compound 220 after purification by reverse-phase HPLC.

Example 221

Compound 221

To a stirred solution of 12.4 mL of 0.5 M sodium methoxide in methanol was added hydroxylamine hydrochloride. Once the solid dissolved, the solution was added to a solution of 530 mg (1.24 mmol) of compound 207 in 5 mL of methanol at room temperature. The resulting mixture was allowed to stir overnight under a nitrogen atmosphere at room temperature. At this point, the solvent was evaporated in vacuo and the product was purified by flash chromatography (eluent 10% methanol in dichloromethane). Product containing fractions were evaporated in vacuo and the residue was then lyophilized from water to afford compound 221.

30997 / H

145 ¹ H NMR (CDCl ₃ , d): 9.60 (s, 1H), 8.60-7.10 (m, 12H), 5.80 (bs, 1H), 4.40 (m,

1H), 4.45 (s, 3H), 3.15-2.80 (m, 3H), 1.15 (d, J = 7.9 Hz, 3H).

MS: (M + H) + (calc) = 463, found (FAB) = 463.

Example 222

Compound 222

Treatment of compound 208 in a manner similar to Example 221 above for compound 207 gave compound 222 after purification by flash chromatography.

¹ H NMR (methanol-d ₄ , d): 8.69 (m, 1H), 8.35 (m, 1H), 8.00-7.75 (m, 5H), 7.72-

7.25 (m, 5H), 4.47 (m, 1H), 3.57 (9s, 3H), 3.15-2.95 (m, 3H), 1.33 (d, J = 7, 9 Hz, 3H).

MS: (M + H) ⁺ (calc) = 463, found (ion spray) = 463.

Example 223

Compound 223

30997 / H

146

To a stirred solution of 319 mg (0.77 mmol) of 204 in 4 mL of 1: 1 methanol / tetrahydrofuran was added 10 mL of 1N sodium hydroxide. The resulting mixture was allowed to stir at room temperature for 2 hours and then acidified with 12 mL of 1N hydrochloric acid. The solid product of compound 223 was filtered off and dried in vacuo.

¹ H NMR (CDCl ₃ , d): 9.30 (bs, 1H), 8.50 (bs, 1H), 8.30-7.80 (m, 6H), 7.65-7.28 ( m, 5H), 4.40 (m, 1H), 3.20-2.85 (m, 3H), 1.33 (d, J = 7.9 Hz, 3H).

Example 224

Compound 224

O-CH ^{X == / X = /} NH O

To a suspension of Compound 223 in 10 mL of cold dichloromethane was added dropwise 0.11 mL (0.77 mmol) of triethylamine at room temperature under a nitrogen atmosphere. After 10 minutes, isopropyl chloroformate (0.77 ml, 0.77 mmol) was added dropwise. After 30 minutes, DMAP (31 mg) was added and the mixture was allowed to stir at room temperature overnight. At this point, the mixture was diluted with dichloromethane and washed with 1N hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product is chromatographed with 40% ethyl acetate in hexanes followed by 70% ethyl acetate in hexanes to give compound 224.

MS: (M + H) ⁺ (calc) = 442, found (ion spray) = 442.

30997 / H

147

Example 225

Compound 225

Treatment of compound 224 in a manner similar to Example 218 above for compound 203 affords compound 225 after purification by reverse-phase HPLC.

¹ H NMR (DMSO-d 6, d): 9.28 (m, 1H), 9.00 (m, 3H), 8.53 (m, 1H), 8.23-7.92 (m, 4H) 7.32 (s, 1H); 7.15 (s, 1H); 7.00 (s, 1H); 4.38 (m, 1H); 4.32 (s, 3H);

2.93 (m, 3H), 1.25 (m, 3H), 0.99 (m, 3H), 0.87 (m, 3H).

MS: M ⁺ (Calc) = 473, Found (FAB) = 473.

Example 226

Compound 226

7.0 g (31 mmol) of ethyl 4-bromobenzoate are dissolved in 100 ml of tetrahydrofuran. To this solution were added 1.0 g (1.0 mmol) of triphenylphosphine palladium (Pd (Ph3P) ₄ ), 592 mg (1.8 mmol) of triethylamine tetrabutylammonium bromide, 3.4 g (61 mmol) of powdered sodium hydroxide and 3.0 g. diethyl (3-pyridyl) borane. The resulting mixture was refluxed for 2.5 hours, allowed to cool to room temperature and evaporated in vacuo. The crude product was added to methanol and chromatographed

30997 / H

148 (eluent is a gradient of 50% ethyl acetate in hexanes to 70% ethyl acetate in hexanes) to give compound 226 after evaporation of the solvent.

¹ H NMR (CDCl ₃ , d): 8.83 (s, 1H), 8.60 (m, 1H), 8.10 (m, 2H), 7.90-7.30 (m, 3H), 4.34 (m, 2H); 1.37 (m, 3H).

Example 227

Compound 227

25.5 ml of 1.0 N sodium hydroxide was added dropwise at room temperature to a stirred solution of 2.7 g (12 mmol) of compound 226 in 21 ml of a 1: 1 mixture of tetrahydrofuran and methanol. After 3 hours, 25 ml of 1N was added. hydrochloric acid and the white precipitate was filtered off. The solid was dried under vacuum to give compound 227.

¹ H NMR (DMSO-d 6, d): 8.90 (s, 1H), 8.60 (s, 1H), 8.13 (m, 1H), 8.05-7.80 (m, 4H) 7.50 (m, IH).

Example 228

Compound 228

ml of thionyl chloride was added to 1.3 g of compound 227. The resulting mixture was refluxed for 2 hours and then evaporated in vacuo to give compound 228.

MS: M + (calculated) = 217, found (EI) = 217.

30997 / H

149

Example 229

Compound 229

A mixture of 10 g (65 mmol) of methylcoumalate, 35 ml (325 mmol) of 4-vinylpyridine and 25 g of 10% palladium on carbon in 200 ml of mesitylene is heated at 200 ° C for 30 hours. At this point, the mixture was allowed to cool and filtered through celite washing with chloroform. Most of the solvent was then evaporated in vacuo and the remaining liquid was chromatographed (eluent was a gradient of 50% ethyl acetate in hexanes to 70% ethyl acetate in hexanes) to give compound 229.

MS: M ⁺ (Calc) = 213, Found (EI) = 213.

Example 230

Compound 230

Treatment of compound 229 with sodium hydroxide in a mixture of tetrahydrofuran and methanol, as in Example 227, provides compound 230.

MS: M ⁺ (Calc) = 199, Found (EI) = 199.

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Example 231

Compound 231

Treatment of compound 230 with refluxing thionyl chloride as in Example 228 affords compound 231.

MS: M ⁺ (Calc) = 217, Found (EI) = 217.

Example 232

Compound 232

BOCNH o

CN

To a solution of 5.57 g (18.1 mmol) of N-Boc-methyl ester of homophenylalanine in 30 ml of tetrahydrofuran at -78 ° C under a nitrogen atmosphere was added dropwise 54.3 ml of a 1N solution of LHMDS in tetrahydrofuran. The mixture is then allowed to warm to 0 C for 30 minutes and then cooled back to -78 C. A solution of 7.46 g (38.0 mmol) of 3-cyanobenzyl bromide in cold tetrahydrofuran is then added dropwise and the resulting solution is allowed to warm to room temperature. After 1 hour at room temperature, the mixture was quenched with saturated sodium bicarbonate solution and most of the tetrahydrofuran was removed in vacuo. The residue was taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulphate, filtered and evaporated. The crude product was purified by flash chromatography (eluent was 25% ethyl acetate in hexanes). The semi-solid residue was then triturated with 20% ethyl acetate in hexanes and the white solid was filtered off. The filtrate was then evaporated in vacuo to give compound 232.

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151 ¹ H NMR (CDCl ₃ , d): 7.82-7.08 (m, 9H), 5.32 (bd, 1H), 3.84 (m, 1H), 3.60 (s, 3H) 3.06-2.57 (m, 5H), 1.70 (m, 2H), 1.47 (s, 9H).

Example 233

Compound 233

TFA.H ₂ NO

Vz ^ CN v

To a stirred solution of Compound 232 (1.42 g, 3.35 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (3.5 mL) at 0 ° C under nitrogen. The mixture was allowed to stir at room temperature for 2 hours and then evaporated in vacuo to give compound 233 as the trifluoroacetate salt.

MS: M ⁺ (Calc) = 322, Found (EI) = 322.

Example 234

Compound 234

OMe

The acylation of compound 233 of Example 203 for compound 228 affords compound 234 after workup and chromatography.

MS: M ⁺ (Calc) = 503, Found (EI) = 503.

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Example 235

Compound 235

Treatment of compound 234 with a mixture of hydrochloric acid and methanol and then ammonium acetate in a similar manner to compound 207 in Example 209 above affords compound 235 after purification by reverse-phase HPLC.

MS: (M + H) ⁺ (calc) = 521, found (FAB) = 521.

Example 236

Compound 236

Treatment of Compound 234 in a similar manner to Compound 203 in Example 218 above affords 236 after purification by reverse-phase HPLC.

¹ H NMR (methanol-d ₄ , d): 9.35 (s, 1H), 8.90 (m, 2H), 8.45 (m, 1H), 8.17 (m, 1H), 8.11-7.92 (m, 4H), 7.68-7.46 (m, 5H), 7.27-7.10 (m, 6H), 4.50 (s, 3H), 4, 40 (m, 1H), 3.57 (s, 3H), 3.05 (m, 3H), 2.67 (m, 2H), 2.00 (m, 2H).

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Example 237

Compound 237

Hydrolysis of compound 234 with sodium hydroxide in a mixture of tetrahydrofuran and methanol using the procedure of Example 227 gave compound 237 after workup.

MS: (M + H) ⁺ (calc) = 490, found (FAB) = 490.

Example 238

Compound 238

. Treatment of Compound 237 in a similar manner to Compound 203 in Example 218 above affords Compound 238 after purification by reverse-phase HPLC.

¹ H NMR (methanol-d ₄ ): 9.38 (s, 1H), 8.90 (m, 2H), 8.47 (m, 1H), 8.17 (m, 1H), 8.11- 7.92 (m, 4H), 7.68-7.46 (m, 5H), 7.26-7.10 (m, 6H), 4.50 (s, 3H), 4.38 (m, 1H), 3.12-2.97 (m, 3H), 2.68 (m, 2H), 2.03 (m, 2H).

The molecules described herein inhibit blood coagulation based on their ability to inhibit the penultimate enzyme in the coagulated cascade, Factor Xa

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154 previous thrombin. Both free factor Xa and factor Xa clustered in the prothrombinase complex (factor Xa, factor Va, calcium and phospholipids) are inhibited. Inhibition of factor Xa is achieved by direct complex formation between the inhibitor and the enzyme and is therefore independent of the antithrombin III plasma cofactor. Effective inhibition of Factor Xa is achieved by administering the compounds either orally, by continuous intravenous infusion, intravenous administration in a single dose, or by some other parenteral route that achieves the desired effect of preventing factor Xa-induced thrombin formation from prothrombin.

Anticoagulant therapy is indicated for the treatment and prophylaxis of various thrombotic conditions, both venous and arterial. In the arterial system, abnormal thrombus formation is associated mainly with the coronary, cerebral and peripheral arteries. Diseases associated with thrombotic congestion of these vessels primarily include acute myocardial infarction (AIM). unstable angina pectoris, thromboembolism, acute vascular occlusion associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemia, stroke, intermittent claudication (occasional curvature) and coronary bypass (CABP) bypass. Chronic anticoagulant therapy may also be useful in preventing vascular lumen constriction (restenosis), which often occurs following PTCA and CABG, and in maintaining vascular accessibility in patients with long-term hemodialysis. Regarding the venous stream, pathological thrombus formation often occurs in the veins of the lower extremities following abdominal, knee and calf operations (DVT). In addition, DVT makes the patient more prone to pulmonary thromboembolism. Systemically disseminated intravascular coagulopathy (DIK) usually occurs in both vascular systems in septic shock, certain viral infections, and tumor. This condition is characterized by rapid consumption of coagulation factors and their plasma inhibitors, resulting in the formation of life-threatening clots in the microcirculation of various organ systems. The indications discussed above include some, but not all, of the possible clinical situations in which it is present

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155 anticoagulant therapy is justified. Those skilled in the art are well aware of circumstances requiring either acute or chronic anticoagulant therapy.

These compounds may be used alone or in combination with another diagnostic, anticoagulant, antiplatelet or fibrinolytic active ingredient. For example, administration of factor Xa inhibitors in conjunction with standard heparin, low molecular weight heparin, direct thrombin inhibitors (i.e., hirudin), aspirin, fibrinogen receptor antagonists, streptokinase, urokinase, and / or tissue plasminogen activator activity may result in thrombin or antitumor activity. The compounds described herein can be administered to treat thrombotic complications in a variety of animals, such as primates, including humans, sheep, horses, cows, pigs, dogs, rats, and mice. Inhibition of factor Xa is not only useful in the anticoagulant treatment of individuals with thrombotic conditions, but is useful whenever it is desired to inhibit blood coagulation, such as to prevent coagulation of stored blood and to prevent coagulation of other biological samples to be tested or stored. Thus, any factor Xa inhibitor may be added to or associated with any medium that contains or could contain factor Xa and in which inhibition of blood coagulation is desired.

In addition to their use in anticoagulant therapy, Factor Xa inhibitors can be used in the treatment or prevention of other diseases in which thrombin formation plays a pathological role. For example, thrombin has been shown to be one of the causes of morbidity and mortality of such chronic and degenerative diseases such as arthritis, cancer, atherosclerosis, and Alzheimer's disease, by virtue of the ability to control many different cell types through specific breakdown and activation of the cell surface thrombin receptor. Inhibition of factor Xa will effectively block thrombin production and thus neutralize some pathological effects of thrombin on various cell types.

According to another aspect of the invention there is provided a method of treating a human or animal suffering from or susceptible to conditions that may be ameliorated by administration of a factor Xa inhibitor, for example, the conditions described above, which

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156 comprises administering to a patient an effective amount of a compound of Formula I or a composition comprising a compound of Formula I. An "effective amount" is understood to describe an amount of a compound of the invention effective to inhibit factor Xa and thereby produce the desired therapeutic effect.

This invention also encompasses pharmaceutical compositions comprising at least one of the compounds of Formula I in association with a pharmaceutically acceptable carrier or coating.

In practice, the compounds of this invention may usually be administered parenterally, intravenously, subcutaneously, intramuscularly, topically, nasally, intraperitoneally, rectally or orally.

The products of the invention may be in forms which allow administration by the most advantageous route, and the invention also relates to pharmaceutical compositions comprising at least one product of the invention which are suitable for use in human or veterinary medicine. These compositions may be prepared according to conventional methods, using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, but are not limited to, diluents, sterile aqueous solvents, and various non-toxic organic solvents. The compositions may take the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more active agents selected from the group consisting of sweetening, flavoring, coloring or stabilizing agents to provide pharmaceutically acceptable compositions. .

The choice of solvent and the active ingredient content of the solvent is usually determined by the solubility and chemical properties of the product, the particular route of administration and the precautions to be followed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and disintegrating agents such as starch, alginic acids, and some complex silicates associated with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used in the preparation of tablets. For the preparation of the capsule

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157 preferably uses lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used, they may contain emulsifying agents or suspending agents. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

For parenteral administration, emulsions, suspensions or solutions of the products of the invention in vegetable oil, for example sesame oil, peanut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, organic esters for injection, such as ethyl oleate, are used, as well as sterile aqueous solutions of pharmaceutically acceptable salts. Salts of the products of the invention are particularly useful for administration intramuscularly or subcutaneously by injection. Aqueous solutions which also include salt solutions in pure distilled water may be used for intravenous administration provided that their pH is appropriately adjusted, that they are reasonably buffered and isotonic with sufficient glucose or sodium chloride, and that they are sterilized by radiation or microfiltration.

Suitable compositions containing the compounds of this invention may be prepared by general methods. For example, the compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or suspension or aerosol solution, or may be absorbed or adsorbed onto an aqueous solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositories prepared by known methods and contain at least one compound of formula

I.

The percentages of the active ingredient in the compositions of the present invention may be varied with the requirement that they should contain such a proportion as to provide an advantageous dosage. Of course, some uniform dosage forms may be administered at about the same time. The dose employed will be determined by the physician and will depend upon the desired therapeutic effect, the route of administration, the time of treatment and the condition of the patient. In an adult, dosages are generally about 0.01 to about 100, preferably about 0.01 to about 10 mg / kg

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158 body weight per day by inhalation, about 0.01 to about 100, preferably about 0.1 to about 70, especially 0.5 to 10 mg / kg body weight per day, orally, and about 0.01 to about 50, preferably about 0.01 up to about 10 mg / kg daily intravenously. In each particular case, dosages will be determined according to factors characteristic of the subject being treated, such as age, weight, general health, and other characteristics that may affect the efficacy of the drug product.

The products of the invention may be administered as often as necessary to achieve the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose and may take much less adequate maintenance doses. For other patients, prolonged treatment at a dose of 1 to 4 doses per day may be required depending on the physiological requirements of each particular patient. Typically, the active product may be administered orally one to four times daily. This can be done without stating that other patients will need to be prescribed no more than one or two doses per day.

The compounds of the invention exhibit significant pharmacological effects according to the tests described in the literature and below and their results are considered to correlate to the pharmacological effect in humans and other mammals.

Enzyme testing

The ability of the compounds of this invention to act as inhibitors of factor Xa, thrombin, trypsin, tissue plasminogen activator (t-PA), urokinase plasminogen activator (µ-PA), plasmin and activated protein C is evaluated by determining the concentrations of inhibitor that causes 50% using purified enzymes. loss of enzyme activity (ΙΟ ₅₀ ).

All enzyme assays are performed at room temperature in a 96-well microtiter plate using a final enzyme concentration of 1 nM. The concentration of factor Xa and thrombin is determined by titration of the active moiety and the concentrations of all other enzymes are based on the protein concentration supplied by the manufacturer. The compounds of this invention are dissolved

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in dimethylsulfoxide, diluted with appropriate buffers and tested at a final dimethylsulfoxide concentration of 1.25%. Dilutions of compounds are added to wells containing buffer and enzyme and allowed to equilibrate for 5 to 30 minutes. Addition of the substrate starts the enzyme reactions and the coloration resulting from the hydrolysis of the peptide-p-nitranilide substrates is continuously monitored for 5 minutes at 405 nm on a Vmax microtiter plate reader (Molecular Devices). Under these conditions, less than 10% of the substrate is used in all assays. Initial measured rates are used to calculate the amount of inhibitor that causes a 50% reduction in control rate (IC ₅₀ ). The apparent K i values are then determined by the Cheng-Prusoff relationship (IC ₅₀ o = Ki [1 + [S] / K _m ] assuming competitive inhibition kinetics.

Additional in vitro assays can be used to determine the efficacy of the compounds of the invention in normal human plasma. Activated partial thromboplastin time is a plasma factor coagulation assay that depends on the formation of factor Xa in situ, its accumulation in the prothrombinase complex, and the subsequent formation of thrombin and fibrin, which eventually provides clot formation as the end point of the assay. This assay is commonly used to clinically monitor the ex vivo effects of the commonly used anticoagulant heparin as well as the direct action of antithrombin agents that are undergoing clinical trials. Thus, efficacy in this in vitro assay is considered to be a surrogate marker for testing in vivo anticoagulant activity.

Testing of coagulation based on the participation of human blood plasma factors

Activated partial thromboplastin coagulation times are determined twice on an MLA Elektra 800 instrument. A volume of 100 μΙ of normal human plasma collected by scitrate (George King Biomedical) is added to a cuvette containing 100 μΙ of a compound of the invention in Tris / NaCl buffer (pH

7.5) and placed in the instrument. After heating the instrument for 3 minutes, 100 μΙ of activated cephaloplastin reagent (Actin, Dade) is added automatically, followed by

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100 μΙ 0.035 Μ CaCl ₂ to initiate the clotting reaction. The precipitate formation is determined spectrophotometrically and measured in seconds. The potency of the compound is quantified as the concentration required to double the control coagulation time measured in blood plasma in the absence of the compound of the invention.

The compounds of the invention can also be evaluated in vivo for antithrombotic activity in two well-established animal experimental models of acute vascular thrombosis. To illustrate the antithrombotic activity of these compounds in human venous and arterial thrombosis in characteristic animal model examples, a rabbit jugular vein thrombosis model and a carotid artery thrombosis model are used, respectively.

Experimental model of rabbit venous thrombosis in vivo

It is a well-described literature-validated model of venous thrombosis with fibrin thrombus formation and has been shown to be sensitive to some anticoagulant drugs including heparin (Holst, J., Lindblad, B., Bergqist, D., Nordfang, O., Ostergaard PB. , Petersen JGL, Nielsen, G. and Hedner U .: Antithrombotic Effect of Recombinant Truncated Tissue Factor Pathway Inhibitor (TFPI 1-161) in Experimental Venous Thrombosis-A Comparison With Low Molecular Weight Heparin In: Thrombosis and Haemostasis, 71, 214- 219 (1994) The purpose of using this model is to evaluate the ability of the compounds to prevent the formation of venous thrombi (clots) formed in vivo at the site of injury and partial stasis in the jugular vein.

r

Male and female New Zealand white rabbits weighing 1.5 to 2 kg are anesthetized with ketamine 35 mg / kg and xylazine 5 mg / kg in a volume of 1 ml / kg (i.m.). An anesthetic infusion cannula (ketamine / xylazine 17 / 2.5 mg / h at a rate of approximately 0.5 ml / h) and the administration of test substances are introduced into the right vein of the jugularis. A cannula is inserted into the right artery of the carotis to record arterial blood pressure and collect blood samples. Body temperature is maintained at 39 ° C with a GAYMAR T-PUMP. The left external jugular vein is isolated and

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all side branches along the revealed 2 to 3 cm vessels are removed. The internal jugular vein is cannulated directly above the jugularis communis vein bifurcation and the cannula tip is moved proximally to the jugularis communis vein. The 1 cm section of the vein is isolated by non-traumatic vascular clamps and the relative stenosis is formed by binding the ligature around the vein with an 18 G puncture as far as possible directly below the clamp. This creates an area of reduced flow and partial stasis at the injured site. The isolated segment is gently rinsed two to three times with sodium chloride solution using a cannula in the internal jugular vein. The isolated segment is then filled with 0.5 ml of 0.5% polyoxyethylene ether (W-1) for 5 minutes. W-1 is a detergent that breaks the endothelial cell junctions of the segment, thereby creating a thrombogenic surface to initiate clot formation. After 5 minutes, W-1 is removed from the segment and the segment is rinsed gently again two to three times with brine. The vascular clamps are then removed and blood flow is restored through this part of the vessel. The clot formation and enlargement are allowed to stand for 30 minutes, then the vein is separated directly under the tapering ligature and examined for blood flow (lack of blood flow is recorded as complete closure). The entire isolated segment of vein is then ligated and the precipitate formed is removed and weighed (wet weight). The effect of the test substances on the final weight of the precipitate is used as the primary end result.

The animals are continued for an additional 30 minutes to obtain a final pharmacodynamic measurement of anticoagulation. Drug administration is initiated 15 minutes prior to W-1 vessel injury and continues during formation and maturation of the clot. Three blood samples (3 ml each) are obtained to assess hemostatic parameters:

r one directly before administration of W-1, the second 30 minutes after removal of the vascular clamps and the third after the end of the experiment. The antithrombotic efficacy of the compounds treated with the compound of the invention appears to decrease the final clot weight relative to vehicle-treated control animals.

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Experimental model of arterial thrombosis in rat in vivo

The antithrombotic efficacy of factor Xa inhibitors of the platelet sagregáciou arterial thrombosis may be evaluated using a well characterized model of thrombosis induced by FeCl ₂ in the carotid artery of the rat (Schumacher WA Heran

C. L., Steinbacher, T. E., Youssef, S., and Ogletree, M.L .: Superior Activity of a Thromboxane Receptor Antagonist Compared with Aspirin in Rat Models of Arterial and Venous Thrombosis. In: Journal of Cardiovascular Pharmacology, 22: 526-533 (1993); Kurtz, K. D., Main, W. W., and Sandusky, G. E., Rat Model of Arterial Thrombosis Induced by Ferric Chloride. In: Thrombosis Research 60: 269-280 (1990); Broersma, R.J., Kutcher, L.W., and Heminger, E. F., The Effect of Thrombin Inhibition in a Rat Arterial Thrombosis Model. In: Thrombosis Research 64: 405-412 (1991). This model is widely used to assess the antithrombotic effect of many active substances including heparin and direct acting thrombin inhibitors.

Sprague-Dawley rats weighing 375-450 g are anesthetized with sodium pentobarbital (50 mg / kg intraperitoneally). When an adequate degree of anesthesia is achieved, the ventral surface of the neck is shaved, ready for aseptic surgery. Electrodes of the electrocardiogram are connected and current conduction monitored during the experiment. A PE-50 cannula is inserted into the right femoral artery and femoral vein to deliver a compound of the invention and to obtain blood samples and to display blood pressure, respectively. The medial incision is made through the ventral area of the neck. Trachea is exposed and intubated with PE-240 tubing to ensure air availability. The right carotid artery is isolated and two silk 4-0 sutures are placed around the vessels to facilitate instrumentation. The electromagnetic radiation probe (lumen 0.95-1.0 mm) is placed around the blood flow vessel. To isolate the vessel from the surrounding muscle layer, a 4 x 4 mm parafilm strip is placed under the vessel distal to the probe. After performing basic flow measurements, a 2x5 mm filter paper previously saturated with 35% FeCl ₂ was placed on top of the vessel downstream of the probe for 10 minutes and then discarded. FeCl ₂ is designed to penetrate the underlying segment of the artery and cause deendothelization leading to formation

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163 acute thrombus. Following application of a FeCfe saturated filter paper, blood pressure is monitored for 60 minutes, blood flow to the carotid artery and cardiac activity. Following vascular occlusion (defined as achieving zero blood flow) or 60 minutes following filter paper application, while access is maintained, the artery is ligated proximally and distally from the wound area and the vessel is excised. Thrombus is removed and weighed immediately and recorded as the primary endpoint of the study.

A control blood sample (B1) is then taken by surgical instrumentation. All blood samples are taken from the arterial catheter and mixed with sodium citrate to prevent coagulation. After each blood sample, the catheter is rinsed with 0.5 ml 0.9% sodium chloride. The compound of the invention is started 5 minutes before FeCl2 administration and is administered intravenously (iv). The time between FeCl administration and the time at which blood flow in the carotid artery reaches zero is recorded as the time required to close the vessel. For vessels that did not close within 60 minutes, the value is reported at 60 minutes. A second blood sample (B2) is taken 5 minutes after application of FeCl _second After exposure to FeCl ₂ for 10 minutes, the filter paper is removed from the vessel and the animal is monitored for the remainder of the experiment. After reaching zero blood flow, a third blood sample (B3) is taken and the clot is removed and weighed. The bleeding time measurements of the samples are made on the tummy of the forelimbs at the same time as blood samples are obtained. Coagulation profiles consisting of activated partial thromboplastin time (APTT) and prothrombin time (PT) are performed on all blood samples. In some cases, the compound of the invention may be administered orally. Rats are manually fixed using standard r

procedures and compounds were administered via intragastric dispensers using an 18 G curved dosing needle (volume 5 ml / kg). Fifteen minutes after intragastric dosing, the animal is anesthetized and instrumented as above. The experiments are then performed as described above.

For example, compound 184 when tested with Factor Xa, Trypsin, and Thrombin shows K values, 27.0 nM, 1.72 M, and 2.71 M, respectively.

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Compound 45, when tested with factor Xa, trypsin and thrombin, shows 94.0 nM, 129 nM, and 477 nM, respectively. Compound 167 when tested with Factor Xa, Trypsin and Thrombin showed values of 19.0 nM, 46 nM, and 1.228 M, respectively.

The present invention may be incorporated into other specific forms without departing from the nature or its essential characteristics.

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Claims (10)

A compound of the general formula wherein: R 1 and R ₂ represent a hydrogen atom or together form a group = NR _g , R3 is -CO2Re, -C (O) R6, -CONReRe, -CH2OR7 or -CH2SR7, R 4 represents a group of the formula or or R 4 represents a hydrogen, alkyl, cycloalkyl or cycloalkylalkyl group, R ₅ represents an alkyl, alkenyl, optionally substituted aryl or optionally substituted heteroaryl group, R ₆ represents a hydrogen atom or a lower alkyl group, R ₇ represents a hydrogen atom, a lower alkyl group, a lower acyl, aroyl or heteroaryl group, R 5 represents a hydrogen atom or a lower alkyl group, 30997 / H 166 R _g represents a group of formula _C-2 Rio0, R10O-, HO-, cyano, R 10 CO-, HCO, lower alkyl, nitro, or Y ¹ Y ² N-, wherein R 10 is an optionally substituted alkyl, optionally substituted aralkyl or an optionally substituted heteroaralkyl group and wherein Y ¹ and Y ² independently represent a hydrogen atom or an alkyl group, A and B are hydrogen or together are a bond, Ar represents an optionally substituted aryl or an optionally substituted heteroaryl group and n is 0, 1 or 2, or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof. A compound according to claim 1, wherein R 1 and R ₂ together form = NH. A compound according to claim 2, wherein R 1 and R ₂ together form = NH and form aminoiminomethyl on the phenyl moiety that is in meta position relative to the position of attachment of the phenyl moiety to the propyl moiety. The compound of claim 1, wherein R ₃ is -CO ₂ R 6. -CH ₂ OR ₇ or -CH ₂ SR ₇ . The compound of claim 4, wherein R ₃ is -CO ₂ R ₆ and R ₆ is lower alkyl. A compound according to claim 4, wherein R ₃ represents -CH ₂ OR ₇ or -CH ₂ SR ₇ and R ₇ represents a hydrogen atom or a lower alkyl. The compound of claim 1, wherein n is 1. The compound of claim 1, wherein Ar is optionally substituted aryl. The compound of claim 1, wherein Ar is phenyl. The compound of claim 1, wherein R ₅ is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, or optionally substituted heterobiphenyl.